VCV001704295.1 - ClinVar

NM_003274.5(TRAPPC10):c.3392del (p.Gly1131fs)

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.

(1)

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

no assertion criteria provided

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_003274.5(TRAPPC10):c.3392del (p.Gly1131fs)

Variation ID: 1704295 Accession: VCV001704295.1

Type and length

Deletion, 1 bp

Location

Cytogenetic: 21q22.3 21: 44102822 (GRCh38) [ NCBI UCSC ] 21: 45522703 (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	Sep 10, 2022	Sep 10, 2022	Sep 7, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_003274.5:c.3392del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003265.3:p.Gly1131fs	frameshift
NM_001351709.1:c.1991del	NP_001338638.1:p.Gly664fs	frameshift
NC_000021.9:g.44102823del
NC_000021.8:g.45522704del
NG_008658.1:g.95499del

... more HGVS ... less HGVS

Protein change

G1131fs, G664fs

Other names

Canonical SPDI

NC_000021.9:44102821:GG:G

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

OMIM: 602103.0002 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.
TRAPPC10		No evidence available	No evidence available	GRCh38 GRCh37	85	199

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.
NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY, SHORT STATURE, SPEECH DELAY, AND BEHAVIORAL ABNORMALITIES	Pathogenic (1)	no assertion criteria provided	Sep 7, 2022	RCV002281664.1

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 (Sep 07, 2022)	no assertion criteria provided Method: literature only	NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY, SHORT STATURE, SPEECH DELAY, AND BEHAVIORAL ABNORMALITIES Affected status: not provided Allele origin: germline	OMIM Accession: SCV002570099.1 First in ClinVar: Sep 10, 2022 Last updated: Sep 10, 2022	Publications: PubMed (1) PubMed: 35298461 Comment on evidence: In 8 affected members of a consanguineous Pakistani family (family 1) with neurodevelopmental disorder with microcephaly, short stature, and speech delay (NEDMISS; 620027), Rawlins et … (more) In 8 affected members of a consanguineous Pakistani family (family 1) with neurodevelopmental disorder with microcephaly, short stature, and speech delay (NEDMISS; 620027), Rawlins et al. (2022) identified a homozygous 1-bp deletion (c.3392delG, NM_003274.4) in the penultimate exon of the TRAPPC10 gene, resulting in frameshift and premature termination of the protein (Gly1131ValfsTer19). The mutation, which was found by a combination of homozygosity mapping and exome sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. In vitro functional expression studies in yeast showed that the mutant protein had reduced interaction with TRAPPC2L (610970) compared to controls. Studies on a patient-derived lymphoblastoid cell line showed absence of the TRAPPC10 protein, as well as absence of full-length TRAPPC9 (611966), an interacting protein. The mutant protein was unable to fully rescue Golgi membrane trafficking defects in TRAPPC10-null HEK293 cells, whereas expression of wildtype TRAPPC10 could rescue the phenotype. The findings were consistent with the mutation causing partial functional defects. There was also evidence that the mutant protein was subject to enhanced degradation within the cell. Other features included hypotonia and behavioral abnormalities; 4 patients had seizures. (less)

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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Biallelic variants in TRAPPC10 cause a microcephalic TRAPPopathy disorder in humans and mice.	Rawlins LE	PLoS genetics	2022	PMID: 35298461

Text-mined citations for this variant ...

Record last updated Sep 17, 2022

ClinVar Genomic variation as it relates to human health

NM_003274.5(TRAPPC10):c.3392del (p.Gly1131fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...