X-6533785-A-G

Position:

• chrX-6533785-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000381089.7(VCX3A):​c.521T>C​(p.Leu174Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., 0 hem., cov: 18)
  • Exomes 𝑓: 0.000059 (0 hom. 11 hem.)
  • Failed GnomAD Quality Control
• Consequence: VCX3A ENST00000381089.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.723

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006362945).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VCX3A	NM_016379.4	c.521T>C	p.Leu174Pro	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.521T>C	p.Leu174Pro	missense_variant	3/3	1	NM_016379.4	ENSP00000370479.3
VCX3A	ENST00000398729.1	c.461T>C	p.Leu154Pro	missense_variant	4/4	5		ENSP00000381713.1

Frequencies

GnomAD3 genomes AF: 0.000483 AC: 48 AN: 99443 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 26445

Gnomad AFR AF: 0.00115

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000214

Gnomad ASJ AF: 0.000832

Gnomad EAS AF: 0.000302

Gnomad SAS AF: 0.000962

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000187

Gnomad OTH AF: 0.000773

GnomAD3 exomes AF: 0.000228 AC: 41 AN: 179547 Hom.: 0 AF XY: 0.0000453 AC XY: 3 AN XY: 66191

Gnomad AFR exome AF: 0.000549

Gnomad AMR exome AF: 0.0000370

Gnomad ASJ exome AF: 0.000135

Gnomad EAS exome AF: 0.000297

Gnomad SAS exome AF: 0.000108

Gnomad FIN exome AF: 0.000630

Gnomad NFE exome AF: 0.000175

Gnomad OTH exome AF: 0.000450

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000594 AC: 61 AN: 1026305 Hom.: 0 Cov.: 39 AF XY: 0.0000324 AC XY: 11 AN XY: 339729

Gnomad4 AFR exome AF: 0.0000786

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000113

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000619

Gnomad4 FIN exome AF: 0.000138

Gnomad4 NFE exome AF: 0.0000580

Gnomad4 OTH exome AF: 0.0000705

GnomAD4 genome AF: 0.000483 AC: 48 AN: 99474 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 26494

Gnomad4 AFR AF: 0.00115

Gnomad4 AMR AF: 0.000214

Gnomad4 ASJ AF: 0.000832

Gnomad4 EAS AF: 0.000303

Gnomad4 SAS AF: 0.000964

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000187

Gnomad4 OTH AF: 0.000763

Alfa AF: 0.000927 Hom.: 2

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00253 AC: 301

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2024

The c.521T>C (p.L174P) alteration is located in exon 3 (coding exon 2) of the VCX3A gene. This alteration results from a T to C substitution at nucleotide position 521, causing the leucine (L) at amino acid position 174 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	15
DANN	Benign	0.41
DEOGEN2	Benign	0.010	T;.
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.28	T;T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.0064	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.012
Sift	Benign	0.063	T;D
Sift4G	Benign	0.20	T;T
Polyphen		0.0060	B;.
Vest4		0.053
MVP		0.043
MPC		0.43
ClinPred		0.0084	T
GERP RS		0.59
Varity_R		0.29
gMVP		0.0023

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: rs144497136; hg19: chrX-6451826; COSMIC: COSV99059333;