X-6533888-C-G

Variant names:

• chrX-6533888-C-G
• rs72609545
• NM_016379.4:c.418G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_016379.4(VCX3A):​c.418G>C​(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. 14/19 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: 𝑓 0.000015 (0 hom., 0 hem., cov: 13)
  • Exomes 𝑓: 0.000013 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: VCX3A NM_016379.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.36
• Publications: 14 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057854354).

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0000148 AC: 1 AN: 67361 Hom.: 0 Cov.: 13

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000481

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000128 AC: 5 AN: 392086 Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0 AN XY: 151510

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

African (AFR) AF: 0.00 AC: 0 AN: 7246

American (AMR) AF: 0.00 AC: 0 AN: 13067

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9253

East Asian (EAS) AF: 0.0000551 AC: 1 AN: 18157

South Asian (SAS) AF: 0.0000389 AC: 1 AN: 25689

European-Finnish (FIN) AF: 0.0000381 AC: 1 AN: 26253

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1310

European-Non Finnish (NFE) AF: 0.00000738 AC: 2 AN: 271041

Other (OTH) AF: 0.00 AC: 0 AN: 20070

⚠️ 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.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000148 AC: 1 AN: 67361 Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0 AN XY: 15121

African (AFR) AF: 0.00 AC: 0 AN: 12191

American (AMR) AF: 0.00 AC: 0 AN: 7320

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1755

East Asian (EAS) AF: 0.000481 AC: 1 AN: 2081

South Asian (SAS) AF: 0.00 AC: 0 AN: 1293

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3899

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 149

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 37254

Other (OTH) AF: 0.00 AC: 0 AN: 914

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.000354 AC: 14

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	T
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.16
DANN	Benign	0.24
DEOGEN2	Benign	0.0066	T;.
FATHMM_MKL	Benign	0.0016	N
LIST_S2	Benign	0.41	T;T
MetaRNN	Benign	0.0058	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.97	N;.
PhyloP100		-4.4
PrimateAI	Benign	0.48	T
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	T
Varity_R		0.11
gMVP		0.0032
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs72609545; hg19: chrX-6451929;