NM_016628.5:c.267_268dupGG

Variant names:

• chr10-28535748-A-AGG
• rs864321691
• NM_016628.5:c.267_268dupGG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_016628.5(WAC):​c.267_268dupGG​(p.Asp90GlyfsTer103) 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 (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: WAC NM_016628.5 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.55
• Publications: 0 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 11 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 10-28535748-A-AGG is Pathogenic according to our data. Variant chr10-28535748-A-AGG is described in ClinVar as Pathogenic. ClinVar VariationId is 219141.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WAC	NM_016628.5	c.267_268dupGG	p.Asp90GlyfsTer103	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.267_268dupGG	p.Asp90GlyfsTer103	frameshift_variant	Exon 3 of 14	1	NM_016628.5	ENSP00000346986.4
WAC	ENST00000428935.6	c.132_133dupGG	p.Asp45GlyfsTer103	frameshift_variant	Exon 3 of 8	2		ENSP00000399706.3
WAC	ENST00000651885.1	c.285_286dupGG	p.Asp96GlyfsTer77	frameshift_variant	Exon 3 of 5			ENSP00000498678.1
WAC	ENST00000651598.1	c.132_133dupGG	p.Asp45GlyfsTer103	frameshift_variant	Exon 3 of 6			ENSP00000498480.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Nov 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs864321691; hg19: chr10-28824677;