VCV001705857.2 - ClinVar

NM_003551.3(NME5):c.572G>A (p.Trp191Ter)

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.

(2)

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.

Likely pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_003551.3(NME5):c.572G>A (p.Trp191Ter)

Variation ID: 1705857 Accession: VCV001705857.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q31.2 5: 138115748 (GRCh38) [ NCBI UCSC ] 5: 137451437 (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 17, 2022	Mar 18, 2023	Feb 23, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_003551.3:c.572G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003542.1:p.Trp191Ter	nonsense
NC_000005.10:g.138115748C>T
NC_000005.9:g.137451437C>T

Protein change

W191*

Other names

Canonical SPDI

NC_000005.10:138115747:C:T

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: 603575.0001 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.
NME5		-	-	GRCh38 GRCh37	12	32

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.
Ciliary dyskinesia, primary, 48, without situs inversus	Likely pathogenic (2)	criteria provided, single submitter	Feb 23, 2023	RCV002284165.2

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.
Likely pathogenic (Feb 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ciliary dyskinesia, primary, 48, without situs inversus Affected status: yes Allele origin: unknown	3billion Accession: SCV003841664.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). This variant was predicted to result in … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). This variant was predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Recurrent sinusitis (present) , Asthma (present) , Bronchiectasis (present) , Recurrent pneumonia (present) , Recurrent respiratory infections (present)
Pathogenic (Sep 15, 2022)	no assertion criteria provided Method: literature only	CILIARY DYSKINESIA, PRIMARY, 48, WITHOUT SITUS INVERSUS Affected status: not provided Allele origin: germline	OMIM Accession: SCV002573545.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Publications: PubMed (1) PubMed: 32185794 Comment on evidence: In a 38-year-old Korean woman with primary ciliary dyskinesia-48 without situs inversus (CILD48; 620032), Cho et al. (2020) identified a homozygous c.572G-A transition (c.572G-A, NM_003551.3) … (more) In a 38-year-old Korean woman with primary ciliary dyskinesia-48 without situs inversus (CILD48; 620032), Cho et al. (2020) identified a homozygous c.572G-A transition (c.572G-A, NM_003551.3) in exon 6 of the NME5 gene, resulting in a trp191-to-ter (W191X) substitution in the DPY-30 domain, which is important for the assembly of radial spokes in cilia. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was present at a low frequency in the East Asian population in gnomAD (1.88 x 10(-4)) and in a Korean control database (0.003215). The mutation occurred in the last exon and was thus predicted to escape nonsense-mediated mRNA decay, but studies of patient cells could not be performed. Functional studies of the variant were also not performed. Patient respiratory motile cilia showed absence of the central pair (CP) of microtubules, and the authors suggested that a defect in NME5 may cause an absence of the radial spoke head, which leads to the CP abnormality. (less)

Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). This variant was predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

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
A nonsense variant in NME5 causes human primary ciliary dyskinesia with radial spoke defects.	Cho EH	Clinical genetics	2020	PMID: 32185794

Text-mined citations for this variant ...

Record last updated Jun 04, 2023

ClinVar Genomic variation as it relates to human health

NM_003551.3(NME5):c.572G>A (p.Trp191Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...