rs202138217

Variant names:

• chrX-8465853-C-T
• rs202138217
• NM_001001888.4:c.211C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001001888.4(VCX3B):​c.211C>T​(p.Pro71Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 12)
  • Exomes 𝑓: 0.000083 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: VCX3B NM_001001888.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.38
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11851525).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCX3B	NM_001001888.4	c.211C>T	p.Pro71Ser	missense_variant	Exon 3 of 3	ENST00000381032.6	NP_001001888.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCX3B	ENST00000381032.6	c.211C>T	p.Pro71Ser	missense_variant	Exon 3 of 3	5	NM_001001888.4	ENSP00000370420.1

Frequencies

GnomAD3 genomes Cov.: 12

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000834 AC: 83 AN: 994844 Hom.: 0 Cov.: 30 AF XY: 0.00000337 AC XY: 1 AN XY: 296762

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25457

American (AMR) AF: 0.00 AC: 0 AN: 33820

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17439

East Asian (EAS) AF: 0.00 AC: 0 AN: 29638

South Asian (SAS) AF: 0.00 AC: 0 AN: 48376

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36381

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2571

European-Non Finnish (NFE) AF: 0.000104 AC: 79 AN: 758621

Other (OTH) AF: 0.0000940 AC: 4 AN: 42541

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 12

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 28, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.211C>T (p.P71S) 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 211, causing the proline (P) at amino acid position 71 to be replaced by a serine (S). 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	0.092
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.1
DANN	Benign	0.92
DEOGEN2	Benign	0.0079	.;T;.;.
FATHMM_MKL	Benign	0.0023	N
LIST_S2	Benign	0.75	T;T;T;T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	.;M;.;.
PhyloP100		-3.4
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.0	N;N;N;N
REVEL	Benign	0.018
Sift	Uncertain	0.0080	D;T;D;T
Sift4G	Uncertain	0.053	T;T;D;D
Polyphen		0.50	.;P;.;.
Vest4		0.068
MutPred		0.17		Gain of phosphorylation at P71 (P = 0.0042);Gain of phosphorylation at P71 (P = 0.0042);Gain of phosphorylation at P71 (P = 0.0042);Gain of phosphorylation at P71 (P = 0.0042);
MVP		0.055
MPC		0.93
ClinPred		0.47	T
GERP RS		-0.31
Varity_R		0.037
gMVP		0.014
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs202138217; hg19: chrX-8433894;