VCV000529908.13 - ClinVar

NM_004329.3(BMPR1A):c.44_47del (p.Leu15fs)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(4)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004329.3(BMPR1A):c.44_47del (p.Leu15fs)

Variation ID: 529908 Accession: VCV000529908.13

Type and length

Deletion, 4 bp

Location

Cytogenetic: 10q23.2 10: 86876060-86876063 (GRCh38) [ NCBI UCSC ] 10: 88635817-88635820 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	May 1, 2024	Jan 23, 2020

HGVS

Nucleotide	Protein	Molecular consequence
NM_004329.3:c.44_47del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004320.2:p.Leu15fs	frameshift
NM_004329.2:c.44_47delTGTT		frameshift
NC_000010.11:g.86876062_86876065del
NC_000010.10:g.88635819_88635822del
NG_009362.1:g.124424_124427del
LRG_298:g.124424_124427del
LRG_298t1:c.44_47del	LRG_298p1:p.Leu15fs

... more HGVS ... less HGVS

Protein change

L15fs

Other names

Canonical SPDI

NC_000010.11:86876059:TTTGTT:TT

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA658797453 OMIM: 601299.0001 dbSNP: rs1554886816 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
BMPR1A		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2329	2425

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Generalized juvenile polyposis/juvenile polyposis coli	Pathogenic (1)	criteria provided, single submitter	-	RCV000635432.5
Juvenile polyposis syndrome	Pathogenic (2)	criteria provided, single submitter	Jan 23, 2020	RCV001376603.8
Hereditary cancer-predisposing syndrome	Pathogenic (1)	criteria provided, single submitter	Dec 31, 2018	RCV002331136.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Juvenile polyposis syndrome Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV001424375.1 First in ClinVar: Jul 25, 2020 Last updated: Jul 25, 2020
Pathogenic (Jan 23, 2020)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Juvenile polyposis syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000756845.7 First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 28492532‚ 11536076‚ 12417513‚ 11381269‚ 23399955 Comment: For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in BMPR1A are known to be pathogenic (PMID: 11536076, 12417513). This variant has … (more) For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in BMPR1A are known to be pathogenic (PMID: 11536076, 12417513). This variant has been reported in individuals affected with juvenile polyposis and colon cancer (PMID: 11381269) and has been reported to segregate with juvenile polyposis syndrome (JPS) in a single family (PMID: 23399955). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Leu15Serfs*20) in the BMPR1A gene. It is expected to result in an absent or disrupted protein product. (less)
Pathogenic (Dec 31, 2018)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002629111.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 11381269‚ 23399955 Comment: The c.44_47delTGTT pathogenic mutation, located in coding exon 1 of the BMPR1A gene, results from a deletion of 4 nucleotides at nucleotide positions 44 to … (more) The c.44_47delTGTT pathogenic mutation, located in coding exon 1 of the BMPR1A gene, results from a deletion of 4 nucleotides at nucleotide positions 44 to 47, causing a translational frameshift with a predicted alternate stop codon (p.L15Sfs*20). This alteration segregated with disease in 8 members of a juvenile polyposis family and was not seen in four unaffected family members (Howe JR et al. Nat. Genet., 2001 Jun;28:184-7). It was also seen in two patients with juvenile polyps who also had colon cancer ( (Ngeow J et al. Gastroenterology, 2013 Jun;144:1402-9, 1409.e1-5). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Jun 01, 2001)	no assertion criteria provided Method: literature only	JUVENILE POLYPOSIS SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000028921.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (1) PubMed: 11381269 Comment on evidence: In a kindred with juvenile polyposis (174900), Howe et al. (2001) found that affected members had a 4-bp deletion in exon 1 (44-47delTGTT) of the … (more) In a kindred with juvenile polyposis (174900), Howe et al. (2001) found that affected members had a 4-bp deletion in exon 1 (44-47delTGTT) of the BMPR1A gene, resulting in a stop codon at nucleotides 104-106. (less)

Comment:

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in BMPR1A are known to be pathogenic (PMID: 11536076, 12417513). This variant has been reported in individuals affected with juvenile polyposis and colon cancer (PMID: 11381269) and has been reported to segregate with juvenile polyposis syndrome (JPS) in a single family (PMID: 23399955). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Leu15Serfs*20) in the BMPR1A gene. It is expected to result in an absent or disrupted protein product.

Comment:

The c.44_47delTGTT pathogenic mutation, located in coding exon 1 of the BMPR1A gene, results from a deletion of 4 nucleotides at nucleotide positions 44 to 47, causing a translational frameshift with a predicted alternate stop codon (p.L15Sfs*20). This alteration segregated with disease in 8 members of a juvenile polyposis family and was not seen in four unaffected family members (Howe JR et al. Nat. Genet., 2001 Jun;28:184-7). It was also seen in two patients with juvenile polyps who also had colon cancer ( (Ngeow J et al. Gastroenterology, 2013 Jun;144:1402-9, 1409.e1-5). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Prevalence of germline PTEN, BMPR1A, SMAD4, STK11, and ENG mutations in patients with moderate-load colorectal polyps.	Ngeow J	Gastroenterology	2013	PMID: 23399955
Germline SMAD4 or BMPR1A mutations and phenotype of juvenile polyposis.	Sayed MG	Annals of surgical oncology	2002	PMID: 12417513
Germline mutations in BMPR1A/ALK3 cause a subset of cases of juvenile polyposis syndrome and of Cowden and Bannayan-Riley-Ruvalcaba syndromes.	Zhou XP	American journal of human genetics	2001	PMID: 11536076
Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis.	Howe JR	Nature genetics	2001	PMID: 11381269

Text-mined citations for rs1554886816 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_004329.3(BMPR1A):c.44_47del (p.Leu15fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1554886816 ...