Genetic Variant VCX3A:p.Leu174Pro (chrX-6533785-A-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

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

The NM_016379.4(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
NM_016379.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.723

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
VCX3A	NM_016379.4 link	c.521T>C	p.Leu174Pro	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.521T>C	p.Leu174Pro	missense_variant	Exon 3 of 3	1	NM_016379.4	ENSP00000370479.3		Q9NNX9
VCX3A	ENST00000398729.1 link	c.461T>C	p.Leu154Pro	missense_variant	Exon 4 of 4	5		ENSP00000381713.1		E7ESE9

Frequencies

GnomAD3 genomes

AF:

0.000483

AC:

AN:

99443

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

26445

show subpopulations

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:

AN:

179547

Hom.:

AF XY:

0.0000453

AC XY:

AN XY:

66191

show subpopulations

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:

AN:

1026305

Hom.:

Cov.:

AF XY:

0.0000324

AC XY:

AN XY:

339729

show subpopulations

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:

AN:

99474

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

26494

show subpopulations

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.:

ESP6500AA

AF:

0.000522

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.00253

AC:

301

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

BayesDel_noAF

Benign

-0.81

CADD

Benign

DANN

Benign

0.41

DEOGEN2

Benign

0.010

T;.

FATHMM_MKL

Benign

0.0011

LIST_S2

Benign

0.28

T;T

M_CAP

Benign

0.0012

MetaRNN

Benign

0.0064

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

L;.

PrimateAI

Uncertain

0.51

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over