Genetic Variant NM_016628.5:c.14C>T (chr10-28533593-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016628.5(WAC):c.14C>T(p.Ala5Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000696 in 1,436,494 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A5G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

WAC
NM_016628.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.62

Publications

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

WAC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WAC	NM_016628.5	MANE Select	c.14C>T	p.Ala5Val	missense	Exon 1 of 14	NP_057712.2
WAC	NM_100486.4		c.14C>T	p.Ala5Val	missense	Exon 1 of 13	NP_567823.1	Q9BTA9-5
WAC	NM_100264.3		c.-94-405C>T		intron	N/A	NP_567822.1	Q9BTA9-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WAC	ENST00000354911.9	TSL:1 MANE Select	c.14C>T	p.Ala5Val	missense	Exon 1 of 14	ENSP00000346986.4	Q9BTA9-1
WAC	ENST00000651885.1		c.14C>T	p.Ala5Val	missense	Exon 1 of 5	ENSP00000498678.1	A0A494C0S5
WAC	ENST00000375664.8	TSL:1	c.-94-405C>T		intron	N/A	ENSP00000364816.3	Q9BTA9-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.96e-7

AC:

AN:

1436494

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

715028

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31284

American (AMR)

AF:

0.00

AC:

AN:

43532

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25258

East Asian (EAS)

AF:

0.00

AC:

AN:

37446

South Asian (SAS)

AF:

0.00

AC:

AN:

84894

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51052

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5570

European-Non Finnish (NFE)

AF:

9.10e-7

AC:

AN:

1098630

Other (OTH)

AF:

0.00

AC:

AN:

58828

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.076

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.62

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.42

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

PhyloP100

5.6

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-1.6

REVEL

Benign

0.097

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.0010

Vest4

0.72

MutPred

0.30

Gain of sheet (P = 0.0028)

MVP

0.043

MPC

0.42

ClinPred

0.97

GERP RS

1.8

PromoterAI

-0.025

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.61

gMVP

0.37

Mutation Taster

=71/29

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.26

Position offset: -6

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over