chr10-28535741-TAGAG-T

Variant names:

• chr10-28535741-TAGAG-T
• rs864321689
• NM_016628.5:c.263_266delAGAG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_016628.5(WAC):​c.263_266delAGAG​(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 NM_016628.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.38
• Publications: 1 publications found

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]

WAC Gene-Disease associations (from GenCC):

• DeSanto-Shinawi syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• DeSanto-Shinawi syndrome due to WAC point mutation

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Illumina

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId is 219139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WAC	NM_016628.5	c.263_266delAGAG	p.Glu88GlyfsTer103	frameshift_variant	Exon 3 of 14	ENST00000354911.9	NP_057712.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WAC	ENST00000354911.9	c.263_266delAGAG	p.Glu88GlyfsTer103	frameshift_variant	Exon 3 of 14	1	NM_016628.5	ENSP00000346986.4
WAC	ENST00000428935.6	c.128_131delAGAG	p.Glu43GlyfsTer103	frameshift_variant	Exon 3 of 8	2		ENSP00000399706.3
WAC	ENST00000651885.1	c.281_284delAGAG	p.Glu94GlyfsTer77	frameshift_variant	Exon 3 of 5			ENSP00000498678.1
WAC	ENST00000651598.1	c.128_131delAGAG	p.Glu43GlyfsTer103	frameshift_variant	Exon 3 of 6			ENSP00000498480.1

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

Oct 13, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Aug 12, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 219139). -

Inborn genetic diseases Pathogenic:1

May 19, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.4
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs864321689; hg19: chr10-28824670; COSMIC: COSV61568284; COSMIC: COSV61568284;