Genetic Variant WAC:c.42-74G>T (chr10-28533924-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_016628.5(WAC):c.42-74G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000128 in 1,559,938 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

WAC
NM_016628.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.185

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

WAC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

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	Effect	Exon Rank	Protein	UniProt
WAC	NM_016628.5	MANE Select	c.42-74G>T	intron	N/A	NP_057712.2
WAC	NM_100264.3		c.-94-74G>T	intron	N/A	NP_567822.1	Q9BTA9-2
WAC	NM_100486.4		c.42-74G>T	intron	N/A	NP_567823.1	Q9BTA9-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
WAC	ENST00000354911.9	TSL:1 MANE Select	c.42-74G>T	intron	N/A	ENSP00000346986.4	Q9BTA9-1
WAC	ENST00000375664.8	TSL:1	c.-94-74G>T	intron	N/A	ENSP00000364816.3	Q9BTA9-2
WAC	ENST00000428935.6	TSL:2	c.-94-74G>T	intron	N/A	ENSP00000399706.3	A0A0A0MSR1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

7.10e-7

AC:

AN:

1407766

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

702266

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30698

American (AMR)

AF:

0.00

AC:

AN:

42148

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25054

East Asian (EAS)

AF:

0.00

AC:

AN:

37640

South Asian (SAS)

AF:

0.00

AC:

AN:

84404

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51948

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4112

European-Non Finnish (NFE)

AF:

9.31e-7

AC:

AN:

1073592

Other (OTH)

AF:

0.00

AC:

AN:

58170

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

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74348

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.34

(source)

DANN

Benign

0.59

PhyloP100

-0.18

PromoterAI

-0.11

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over