X-8465911-C-T

Position:

• chrX-8465911-C-T

Variant summary

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

The NM_001001888.4(VCX3B):​c.269C>T​(p.Pro90Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., 0 hem., cov: 13)
  • Exomes 𝑓: 0.00018 (0 hom. 2 hem.)
  • Failed GnomAD Quality Control
• Consequence: VCX3B NM_001001888.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.10

Genes affected

VCX3B (HGNC:31838): (variable charge X-linked 3B) 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 the Y-linked members are two identical copies of the gene within a palindromic region on chromosome Yq11. The family members share a high degree of sequence identity, with the exception that a 30-nt 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. This family member, as represented by the reference genome allele, contains 14 copies of the 30-nt repeat unit. VCX/Y genes encode small and highly charged proteins containing putative bipartite nuclear localization signals. Although the exact function of this family member has yet to be determined, a role in mRNA stability regulation can be inferred from the ability of the highly similar family member, VCX-A, to inhibit mRNA decapping. A possible role in the regulation of ribosome assembly during spermatogenesis has also been suggested. [provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06559259).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VCX3B	NM_001001888.4	c.269C>T	p.Pro90Leu	missense_variant	3/3	ENST00000381032.6	NP_001001888.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VCX3B	ENST00000381032.6	c.269C>T	p.Pro90Leu	missense_variant	3/3	5	NM_001001888.4	ENSP00000370420.1

Frequencies

GnomAD3 genomes AF: 0.000160 AC: 14 AN: 87754 Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0 AN XY: 16456

Gnomad AFR AF: 0.0000811

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000130

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000710

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000227

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000176 AC: 10 AN: 56941 Hom.: 0 AF XY: 0.000131 AC XY: 2 AN XY: 15275

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000670

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000128

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000177 AC: 160 AN: 905208 Hom.: 0 Cov.: 23 AF XY: 0.00000780 AC XY: 2 AN XY: 256568

Gnomad4 AFR exome AF: 0.0000454

Gnomad4 AMR exome AF: 0.000238

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000215

Gnomad4 OTH exome AF: 0.0000767

GnomAD4 genome AF: 0.000160 AC: 14 AN: 87754 Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0 AN XY: 16456

Gnomad4 AFR AF: 0.0000811

Gnomad4 AMR AF: 0.000130

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000710

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000227

Gnomad4 OTH AF: 0.00

ExAC AF: 0.000188 AC: 11

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

Dec 20, 2023

The c.269C>T (p.P90L) alteration is located in exon 3 (coding exon 2) of the VCX3B gene. This alteration results from a C to T substitution at nucleotide position 269, causing the proline (P) at amino acid position 90 to be replaced by a leucine (L). 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	0.091
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.94
CADD	Benign	4.6
DANN	Benign	0.90
DEOGEN2	Benign	0.011	.;T;.;.
FATHMM_MKL	Benign	0.00054	N
LIST_S2	Benign	0.72	T;T;T;T
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.066	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	.;L;.;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.6	N;N;N;N
REVEL	Benign	0.0030
Sift	Uncertain	0.016	D;T;D;D
Sift4G	Uncertain	0.028	D;T;D;T
Polyphen		0.019	.;B;.;.
Vest4		0.13
MVP		0.055
MPC		0.94
ClinPred		0.057	T
GERP RS		-0.98
Varity_R		0.037
gMVP		0.0079

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: rs763675939; hg19: chrX-8433952;