dbSNP rs72609545: VCX3A:p.Val140Leu (chrX-6533888-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_016379.4(VCX3A):c.418G>T(p.Val140Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict 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. V140M) has been classified as Benign.

Frequency

Genomes: not found (cov: 13)

Exomes 𝑓: 0.000054 ( 0 hom. 0 hem. )

Consequence

VCX3A
NM_016379.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.36

Publications

0 publications found

Variant links:

Genes affected

VCX3A (HGNC:18159): (variable charge X-linked 3A) This gene belongs to the VCX/Y gene family, which has multiple members on both X and Y chromosomes, and all are expressed exclusively in male germ cells. The X-linked members are clustered on chromosome Xp22 and Y-linked members are two identical copies of the gene within a palindromic region on Yq11. The family members share a high degree of sequence identity, with the exception that a 30-bp unit is tandemly repeated in X-linked members but occurs only once in Y-linked members. The VCX gene cluster is polymorphic in terms of copy number; different individuals may have a different number of VCX genes. VCX/Y genes encode small and highly charged proteins of unknown function. The presence of a putative bipartite nuclear localization signal suggests that VCX/Y members are nuclear proteins. This gene contains 8 repeats of the 30-bp unit. [provided by RefSeq, Jul 2008]

VCX3A links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.07436493).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCX3A	NM_016379.4 link	c.418G>T	p.Val140Leu	missense_variant	Exon 3 of 3	ENST00000381089.7	NP_057463.2	Q9NNX9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCX3A	ENST00000381089.7 link	c.418G>T	p.Val140Leu	missense_variant	Exon 3 of 3	1	NM_016379.4	ENSP00000370479.3		Q9NNX9
VCX3A	ENST00000398729.1 link	c.358G>T	p.Val120Leu	missense_variant, splice_region_variant	Exon 4 of 4	5		ENSP00000381713.1		E7ESE9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000536

AC:

AN:

392037

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

151489

show subpopulations

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

African (AFR)

AF:

0.000138

AC:

AN:

7246

American (AMR)

AF:

0.0000765

AC:

AN:

13064

Ashkenazi Jewish (ASJ)

AF:

0.000108

AC:

AN:

9252

East Asian (EAS)

AF:

0.000331

AC:

AN:

18139

South Asian (SAS)

AF:

0.00

AC:

AN:

25689

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26252

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1309

European-Non Finnish (NFE)

AF:

0.0000332

AC:

AN:

271020

Other (OTH)

AF:

0.000150

AC:

AN:

20066

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 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: 0.254

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.19

(source)

DANN

Benign

0.27

DEOGEN2

Benign

0.0066

T;.

FATHMM_MKL

Benign

0.0018

LIST_S2

Benign

0.41

T;T

M_CAP

Benign

0.0011

MetaRNN

Benign

0.074

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.97

N;.

PhyloP100

-4.4

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.012

Sift

Benign

0.21

T;T

Sift4G

Benign

0.39

T;T

Polyphen

0.039

B;.

Vest4

0.038

MutPred

0.20

Gain of helix (P = 0.0425);.;

MVP

0.043

MPC

0.26

ClinPred

0.22

Varity_R

0.11

gMVP

0.0032

Mutation Taster

=98/2

polymorphism

(source)

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over