10-28535741-TAGAG-T

Position:

• chr10-28535741-TAGAG-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000354911.9(WAC):​c.263_266del​(p.Glu88GlyfsTer103) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: WAC ENST00000354911.9 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.38

Genes affected

WAC (HGNC:17327): (WW domain containing adaptor with coiled-coil) The protein encoded by this gene contains a WW domain, which is a protein module found in a wide range of signaling proteins. This domain mediates protein-protein interactions and binds proteins containing short linear peptide motifs that are proline-rich or contain at least one proline. This gene product shares 94% sequence identity with the WAC protein in mouse, however, its exact function is not known. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-28535741-TAGAG-T is Pathogenic according to our data. Variant chr10-28535741-TAGAG-T is described in ClinVar as [Pathogenic]. Clinvar id is 219139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-28535741-TAGAG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WAC	NM_016628.5	c.263_266del	p.Glu88GlyfsTer103	frameshift_variant	3/14	ENST00000354911.9	NP_057712.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WAC	ENST00000354911.9	c.263_266del	p.Glu88GlyfsTer103	frameshift_variant	3/14	1	NM_016628.5	ENSP00000346986	P3

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 12, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 219139). This premature translational stop signal has been observed in individual(s) with WAC-related conditions (PMID: 25356899). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu88Glyfs*103) in the WAC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in WAC are known to be pathogenic (PMID: 26264232, 26757981). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 13, 2022	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33004838, 30564305, 25356899) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 19, 2023

The c.263_266delAGAG (p.E88Gfs*103) alteration, located in coding exon 3 of the WAC gene, results from a deletion of 4 nucleotides from position 263 to 266, causing a translational frameshift with a predicted alternate stop codon after 103 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was reported de novo in a 30 year old female with moderate intellectual disability, short 5th metacarpals, and minor dysmorphic features (Hamdan, 2014). Based on the available evidence, this alteration is classified as pathogenic. -

DeSanto-Shinawi syndrome due to WAC point mutation Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs864321689; hg19: chr10-28824670;