X-10067337-C-T

Position:

• chrX-10067337-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015691.5(WWC3):​c.439C>T​(p.Arg147Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000638 in 1,097,374 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000064 (0 hom. 1 hem.)
• Consequence: WWC3 NM_015691.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.90

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40972173).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WWC3	NM_015691.5	c.439C>T	p.Arg147Cys	missense_variant	4/24		NP_056506.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WWC3	ENST00000380861.10	c.439C>T	p.Arg147Cys	missense_variant	4/24	1		ENSP00000370242.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000638 AC: 7 AN: 1097374 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 1 AN XY: 362786

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000594

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

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

Nov 30, 2021

The c.67C>T (p.R23C) alteration is located in exon 3 (coding exon 2) of the WWC3 gene. This alteration results from a C to T substitution at nucleotide position 67, causing the arginine (R) at amino acid position 23 to be replaced by a cysteine (C). 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	0.19
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.079	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.46
MVP		0.54
MPC		1.2
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.65
gMVP		0.32

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: rs1233862591; hg19: chrX-10035377;