rs864321689

chr10-28535741-TAGAG-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_016628.5(WAC):c.263_266del(p.Glu88GlyfsTer103) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: WAC NM_016628.5 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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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	UniProt
WAC	NM_016628.5	c.263_266del	p.Glu88GlyfsTer103	frameshift_variant	3/14	ENST00000354911.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WAC	ENST00000354911.9	c.263_266del	p.Glu88GlyfsTer103	frameshift_variant	3/14	1	NM_016628.5	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	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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). -

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;