rs200552602

Positions:

• chrX-6533888-C-T
• chrX-6533888-C-G
• chrX-6533888-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_016379.4(VCX3A):​c.418G>A​(p.Val140Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (0 hom., 0 hem., cov: 13)
  • Exomes 𝑓: 0.0015 (0 hom. 15 hem.)
  • Failed GnomAD Quality Control
• Consequence: VCX3A NM_016379.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.36

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0084787905).
• BP6: Variant X-6533888-C-T is Benign according to our data. Variant chrX-6533888-C-T is described in ClinVar as [Benign]. Clinvar id is 218736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-6533888-C-T is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VCX3A	NM_016379.4	c.418G>A	p.Val140Met	missense_variant	3/3	ENST00000381089.7	NP_057463.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VCX3A	ENST00000381089.7	c.418G>A	p.Val140Met	missense_variant	3/3	1	NM_016379.4	ENSP00000370479.3
VCX3A	ENST00000398729.1	c.358G>A	p.Val120Met	missense_variant, splice_region_variant	4/4	5		ENSP00000381713.1

Frequencies

GnomAD3 genomes AF: 0.00696 AC: 462 AN: 66340 Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0 AN XY: 14768

Gnomad AFR AF: 0.0136

Gnomad AMI AF: 0.00198

Gnomad AMR AF: 0.00700

Gnomad ASJ AF: 0.00463

Gnomad EAS AF: 0.00678

Gnomad SAS AF: 0.00156

Gnomad FIN AF: 0.00338

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00549

Gnomad OTH AF: 0.0111

GnomAD3 exomes AF: 0.0432 AC: 1218 AN: 28216 Hom.: 4 AF XY: 0.00114 AC XY: 13 AN XY: 11360

Gnomad AFR exome AF: 0.0898

Gnomad AMR exome AF: 0.00665

Gnomad ASJ exome AF: 0.0233

Gnomad EAS exome AF: 0.0300

Gnomad SAS exome AF: 0.00722

Gnomad FIN exome AF: 0.157

Gnomad NFE exome AF: 0.0359

Gnomad OTH exome AF: 0.0181

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00154 AC: 598 AN: 388549 Hom.: 0 Cov.: 13 AF XY: 0.000101 AC XY: 15 AN XY: 149135

Gnomad4 AFR exome AF: 0.00308

Gnomad4 AMR exome AF: 0.00108

Gnomad4 ASJ exome AF: 0.00131

Gnomad4 EAS exome AF: 0.00178

Gnomad4 SAS exome AF: 0.000983

Gnomad4 FIN exome AF: 0.00371

Gnomad4 NFE exome AF: 0.00137

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00700 AC: 464 AN: 66319 Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0 AN XY: 14779

Gnomad4 AFR AF: 0.0136

Gnomad4 AMR AF: 0.00713

Gnomad4 ASJ AF: 0.00463

Gnomad4 EAS AF: 0.00680

Gnomad4 SAS AF: 0.00158

Gnomad4 FIN AF: 0.00338

Gnomad4 NFE AF: 0.00549

Gnomad4 OTH AF: 0.0111

ExAC AF: 0.0240 AC: 950

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Mar 06, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.66
DANN	Benign	0.62
DEOGEN2	Benign	0.0069	T;.
FATHMM_MKL	Benign	0.00038	N
LIST_S2	Benign	0.51	T;T
MetaRNN	Benign	0.0085	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.55	N;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.014
Sift	Benign	0.098	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.28	B;.
Vest4		0.047
MPC		0.27
ClinPred		0.0020	T
Varity_R		0.19
gMVP		0.0044

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: rs72609545; hg19: chrX-6451929; COSMIC: COSV66910357;