X-10067421-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_015691.5(WWC3):c.523G>A(p.Glu175Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00844 in 1,207,131 control chromosomes in the GnomAD database, including 34 homozygotes. There are 3,237 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0058 (2 hom., 193 hem., cov: 23)
  • Exomes 𝑓: 0.0087 (32 hom. 3044 hem.)
• Consequence: WWC3 NM_015691.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.80

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0071413517).
• BP6: Variant X-10067421-G-A is Benign according to our data. Variant chrX-10067421-G-A is described in ClinVar as [Benign]. Clinvar id is 773099.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WWC3	NM_015691.5	c.523G>A	p.Glu175Lys	missense_variant	4/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WWC3	ENST00000380861.10	c.523G>A	p.Glu175Lys	missense_variant	4/24	1		P1

Frequencies

GnomAD3 genomes AF: 0.00579 AC: 648 AN: 111922 Hom.: 2 Cov.: 23 AF XY: 0.00566 AC XY: 193 AN XY: 34092

Gnomad AFR AF: 0.00143

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000664

Gnomad ASJ AF: 0.00188

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00150

Gnomad FIN AF: 0.00576

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.0102

Gnomad OTH AF: 0.00668

GnomAD3 exomes AF: 0.00539 AC: 942 AN: 174610 Hom.: 1 AF XY: 0.00503 AC XY: 301 AN XY: 59824

Gnomad AFR exome AF: 0.00103

Gnomad AMR exome AF: 0.000782

Gnomad ASJ exome AF: 0.00177

Gnomad EAS exome AF: 0.0000747

Gnomad SAS exome AF: 0.000964

Gnomad FIN exome AF: 0.00659

Gnomad NFE exome AF: 0.00983

Gnomad OTH exome AF: 0.00437

GnomAD4 exome AF: 0.00871 AC: 9542 AN: 1095155 Hom.: 32 Cov.: 31 AF XY: 0.00844 AC XY: 3044 AN XY: 360769

Gnomad4 AFR exome AF: 0.000759

Gnomad4 AMR exome AF: 0.000858

Gnomad4 ASJ exome AF: 0.00171

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00140

Gnomad4 FIN exome AF: 0.00615

Gnomad4 NFE exome AF: 0.0105

Gnomad4 OTH exome AF: 0.00607

GnomAD4 genome AF: 0.00579 AC: 648 AN: 111976 Hom.: 2 Cov.: 23 AF XY: 0.00565 AC XY: 193 AN XY: 34156

Gnomad4 AFR AF: 0.00143

Gnomad4 AMR AF: 0.000663

Gnomad4 ASJ AF: 0.00188

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00151

Gnomad4 FIN AF: 0.00576

Gnomad4 NFE AF: 0.0102

Gnomad4 OTH AF: 0.00659

Alfa AF: 0.00561 Hom.: 57

Bravo AF: 0.00485

TwinsUK AF: 0.0116 AC: 43

ALSPAC AF: 0.0114 AC: 33

ESP6500AA AF: 0.00104 AC: 4

ESP6500EA AF: 0.00966 AC: 65

ExAC AF: 0.00509 AC: 617

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 07, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	23
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.011	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.26
Sift	Benign	0.070	T
Sift4G	Benign	0.20	T
Polyphen		1.0	D
Vest4		0.46
MVP		0.21
MPC		0.94
ClinPred		0.014	T
GERP RS		5.3
Varity_R		0.33
gMVP		0.35

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: rs61748714; hg19: chrX-10035461;