dbSNP rs864321692: WAC:p.Ser125* (chr10-28583498-C-A) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_016628.5(WAC):c.374C>A(p.Ser125*) variant causes a stop gained 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)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

WAC
NM_016628.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.57

Publications

1 publications found

Variant links:

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

WAC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 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 10-28583498-C-A is Pathogenic according to our data. Variant chr10-28583498-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 219142.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WAC	NM_016628.5 link	c.374C>A	p.Ser125*	stop_gained	Exon 4 of 14	ENST00000354911.9	NP_057712.2	Q9BTA9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
WAC	ENST00000354911.9 link	c.374C>A	p.Ser125*	stop_gained	Exon 4 of 14	1	NM_016628.5	ENSP00000346986.4	Q9BTA9-1
WAC	ENST00000428935.6 link	c.239C>A	p.Ser80*	stop_gained	Exon 4 of 8	2		ENSP00000399706.3	A0A0A0MSR1
WAC	ENST00000651885.1 link	c.392C>A	p.Ser131*	stop_gained	Exon 4 of 5			ENSP00000498678.1	A0A494C0S5
WAC	ENST00000651598.1 link	c.239C>A	p.Ser80*	stop_gained	Exon 4 of 6			ENSP00000498480.1	A0A494C0C1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1412942

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

702544

African (AFR)

AF:

0.00

AC:

AN:

30888

American (AMR)

AF:

0.00

AC:

AN:

37836

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24868

East Asian (EAS)

AF:

0.00

AC:

AN:

36888

South Asian (SAS)

AF:

0.00

AC:

AN:

78150

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5586

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1088256

Other (OTH)

AF:

0.00

AC:

AN:

58114

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Pathogenic:1

Feb 02, 2015

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.66

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

1.0

MetaRNN

Uncertain

0.67

D;D

PhyloP100

7.6

Vest4

0.66

MVP

0.47

GERP RS

5.8

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over