X-10110011-C-T

Position:

• chrX-10110011-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_015691.5(WWC3):​c.1337C>T​(p.Ala446Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000276 in 1,085,192 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000028 (0 hom. 6 hem.)
• Consequence: WWC3 NM_015691.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.81

Genes affected

WWC3 (HGNC:29237): (WWC family member 3) This gene encodes a member of the WWC family of proteins, which also includes the WWC1 (KIBRA) gene product and the WWC2 gene product. The protein encoded by this gene includes a C2 domain, which is known to mediate homodimerization in the related WWC1 gene product. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WWC3	NM_015691.5	c.1337C>T	p.Ala446Val	missense_variant	10/24		NP_056506.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WWC3	ENST00000380861.10	c.1337C>T	p.Ala446Val	missense_variant	10/24	1		ENSP00000370242.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000182 AC: 3 AN: 164393 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 56673

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000416

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000276 AC: 30 AN: 1085192 Hom.: 0 Cov.: 31 AF XY: 0.0000170 AC XY: 6 AN XY: 353848

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000359

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Alfa AF: 0.000223 Hom.: 0

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000346 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 31, 2024

The c.965C>T (p.A322V) alteration is located in exon 9 (coding exon 8) of the WWC3 gene. This alteration results from a C to T substitution at nucleotide position 965, causing the alanine (A) at amino acid position 322 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0049	T
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.55	N
REVEL	Benign	0.12
Sift	Benign	0.072	T
Sift4G	Benign	0.13	T
Polyphen		0.98	D
Vest4		0.80
MVP		0.38
MPC		0.80
ClinPred		0.54	D
GERP RS		5.6
Varity_R		0.15
gMVP		0.18

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

LitVar

Other links and lift over

dbSNP: rs771338586; hg19: chrX-10078051;