X-6533772-G-T

Variant names:

• chrX-6533772-G-T
• rs749452069
• NM_016379.4:c.534C>A

Variant summary

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

The NM_016379.4(VCX3A):​c.534C>A​(p.Ser178Arg) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 18)
  • Exomes 𝑓: 9.6e-7 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: VCX3A NM_016379.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.756
• Publications: 1 publications found

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

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0744338).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016379.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCX3A	NM_016379.4	MANE Select	c.534C>A	p.Ser178Arg	missense	Exon 3 of 3	NP_057463.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCX3A	ENST00000381089.7	TSL:1 MANE Select	c.534C>A	p.Ser178Arg	missense	Exon 3 of 3	ENSP00000370479.3	Q9NNX9
	VCX3A	ENST00000898738.1		c.534C>A	p.Ser178Arg	missense	Exon 2 of 2	ENSP00000568797.1
	VCX3A	ENST00000398729.1	TSL:5	c.474C>A	p.Ser158Arg	missense	Exon 4 of 4	ENSP00000381713.1	E7ESE9

Frequencies

GnomAD3 genomes Cov.: 18

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.62e-7 AC: 1 AN: 1039071 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 344561

⚠️ 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: 25746

American (AMR) AF: 0.0000301 AC: 1 AN: 33230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17948

East Asian (EAS) AF: 0.00 AC: 0 AN: 28758

South Asian (SAS) AF: 0.00 AC: 0 AN: 48934

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37369

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3254

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 800554

Other (OTH) AF: 0.00 AC: 0 AN: 43278

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 18

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	9.6
DANN	Benign	0.77
DEOGEN2	Benign	0.0084	T
FATHMM_MKL	Benign	0.00057	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.00086	T
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.76
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.035
Sift	Benign	0.041	D
Sift4G	Uncertain	0.039	D
Polyphen		0.0040	B
Vest4		0.081
MutPred		0.16		Loss of phosphorylation at S178 (P = 0.0019)
MVP		0.043
MPC		0.30
ClinPred		0.11	T
Varity_R		0.46
gMVP		0.0032
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: rs749452069; hg19: chrX-6451813;