chrX-6533828-C-T

Position:

• chrX-6533828-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016379.4(VCX3A):​c.478G>A​(p.Val160Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (1 hom., 1 hem., cov: 10)
  • Exomes 𝑓: 0.0047 (2 hom. 71 hem.)
  • Failed GnomAD Quality Control
• Consequence: VCX3A NM_016379.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.446

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018401444).
• BP6: Variant X-6533828-C-T is Benign according to our data. Variant chrX-6533828-C-T is described in ClinVar as [Benign]. Clinvar id is 252705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-6533828-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VCX3A	NM_016379.4	c.478G>A	p.Val160Met	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.478G>A	p.Val160Met	missense_variant	3/3	1	NM_016379.4	ENSP00000370479.3
VCX3A	ENST00000398729.1	c.418G>A	p.Val140Met	missense_variant	4/4	5		ENSP00000381713.1

Frequencies

GnomAD3 genomes AF: 0.164 AC: 7418 AN: 45196 Hom.: 1 Cov.: 10 AF XY: 0.000119 AC XY: 1 AN XY: 8392

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.169

Gnomad EAS AF: 0.206

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.0748

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.152

GnomAD3 exomes AF: 0.0225 AC: 2046 AN: 91027 Hom.: 10 AF XY: 0.000968 AC XY: 31 AN XY: 32033

Gnomad AFR exome AF: 0.0541

Gnomad AMR exome AF: 0.00522

Gnomad ASJ exome AF: 0.00558

Gnomad EAS exome AF: 0.0180

Gnomad SAS exome AF: 0.00521

Gnomad FIN exome AF: 0.0667

Gnomad NFE exome AF: 0.0219

Gnomad OTH exome AF: 0.0134

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00467 AC: 3611 AN: 772846 Hom.: 2 Cov.: 49 AF XY: 0.000290 AC XY: 71 AN XY: 245250

Gnomad4 AFR exome AF: 0.0114

Gnomad4 AMR exome AF: 0.00482

Gnomad4 ASJ exome AF: 0.00740

Gnomad4 EAS exome AF: 0.0256

Gnomad4 SAS exome AF: 0.00486

Gnomad4 FIN exome AF: 0.0430

Gnomad4 NFE exome AF: 0.00304

Gnomad4 OTH exome AF: 0.00836

GnomAD4 genome AF: 0.164 AC: 7410 AN: 45177 Hom.: 1 Cov.: 10 AF XY: 0.000119 AC XY: 1 AN XY: 8395

Gnomad4 AFR AF: 0.172

Gnomad4 AMR AF: 0.172

Gnomad4 ASJ AF: 0.169

Gnomad4 EAS AF: 0.207

Gnomad4 SAS AF: 0.147

Gnomad4 FIN AF: 0.0748

Gnomad4 NFE AF: 0.167

Gnomad4 OTH AF: 0.151

ExAC AF: 0.186 AC: 21966

ClinVar

Significance: Benign

Submissions summary: Benign:4

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	Nov 19, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.1
DANN	Benign	0.25
DEOGEN2	Benign	0.0071	T;.
FATHMM_MKL	Benign	0.00020	N
LIST_S2	Benign	0.54	T;T
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.070
Sift	Benign	0.15	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.89	P;.
Vest4		0.053
MPC		0.27
ClinPred		0.0068	T
GERP RS		-1.0
Varity_R		0.14
gMVP		0.0035

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: rs35874450; hg19: chrX-6451869; COSMIC: COSV66910323;