Genetic Variant WAC:p.Ser125Leu (chr10-28583498-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_016628.5(WAC):c.374C>T(p.Ser125Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000129 in 1,552,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000072 ( 0 hom., cov: 31)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

WAC
NM_016628.5 missense

Scores

Clinical Significance

Not reported in ClinVar

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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (REVEL=0.251).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WAC	NM_016628.5 link	c.374C>T	p.Ser125Leu	missense_variant	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>T	p.Ser125Leu	missense_variant	Exon 4 of 14	1	NM_016628.5	ENSP00000346986.4	Q9BTA9-1
WAC	ENST00000428935.6 link	c.239C>T	p.Ser80Leu	missense_variant	Exon 4 of 8	2		ENSP00000399706.3	A0A0A0MSR1
WAC	ENST00000651885.1 link	c.392C>T	p.Ser131Leu	missense_variant	Exon 4 of 5			ENSP00000498678.1	A0A494C0S5
WAC	ENST00000651598.1 link	c.239C>T	p.Ser80Leu	missense_variant	Exon 4 of 6			ENSP00000498480.1	A0A494C0C1

Frequencies

GnomAD3 genomes

AF:

0.00000716

AC:

AN:

139746

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000752

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

7.08e-7

AC:

AN:

1412944

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

702544

show subpopulations

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:

9.19e-7

AC:

AN:

1088258

Other (OTH)

AF:

0.00

AC:

AN:

58114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000716

AC:

AN:

139746

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

66894

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

36912

American (AMR)

AF:

0.0000752

AC:

AN:

13296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3400

East Asian (EAS)

AF:

0.00

AC:

AN:

4770

South Asian (SAS)

AF:

0.00

AC:

AN:

4490

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7810

Middle Eastern (MID)

AF:

0.00

AC:

AN:

230

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66040

Other (OTH)

AF:

0.00

AC:

AN:

1896

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

1.0

M_CAP

Benign

0.028

PhyloP100

7.6

Vest4

0.80

ClinPred

0.92

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.51

Mutation Taster

=83/17

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over