rs864321689

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr10-28535741-TAGAG-T
• chr10-28535741-TAGAG-TAG

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: Labcorp Genetics (formerly Invitae), Illumina, Orphanet, G2P

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016628.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WAC	NM_016628.5	MANE Select	c.263_266delAGAG	p.Glu88GlyfsTer103	frameshift	Exon 3 of 14	NP_057712.2
	WAC	NM_100264.3		c.128_131delAGAG	p.Glu43GlyfsTer103	frameshift	Exon 3 of 14	NP_567822.1	Q9BTA9-2
	WAC	NM_100486.4		c.263_266delAGAG	p.Glu88GlyfsTer103	frameshift	Exon 3 of 13	NP_567823.1	Q9BTA9-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WAC	ENST00000354911.9	TSL:1 MANE Select	c.263_266delAGAG	p.Glu88GlyfsTer103	frameshift	Exon 3 of 14	ENSP00000346986.4	Q9BTA9-1
	WAC	ENST00000375664.8	TSL:1	c.128_131delAGAG	p.Glu43GlyfsTer103	frameshift	Exon 3 of 14	ENSP00000364816.3	Q9BTA9-2
	WAC	ENST00000428935.6	TSL:2	c.128_131delAGAG	p.Glu43GlyfsTer103	frameshift	Exon 3 of 8	ENSP00000399706.3	A0A0A0MSR1

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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	DeSanto-Shinawi syndrome due to WAC point mutation (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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;