X-6533803-C-T

Variant names:

• chrX-6533803-C-T
• rs1171793924
• NM_016379.4:c.503G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_016379.4(VCX3A):​c.503G>A​(p.Ser168Asn) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S168I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000010 (0 hom., 0 hem., cov: 18)
  • Exomes 𝑓: 0.0000097 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: VCX3A NM_016379.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.07
• Publications: 0 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06278744).

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.503G>A	p.Ser168Asn	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.503G>A	p.Ser168Asn	missense	Exon 3 of 3	ENSP00000370479.3	Q9NNX9
	VCX3A	ENST00000898738.1		c.503G>A	p.Ser168Asn	missense	Exon 2 of 2	ENSP00000568797.1
	VCX3A	ENST00000398729.1	TSL:5	c.443G>A	p.Ser148Asn	missense	Exon 4 of 4	ENSP00000381713.1	E7ESE9

Frequencies

GnomAD3 genomes AF: 0.0000100 AC: 1 AN: 99667 Hom.: 0 Cov.: 18

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000208

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000555 AC: 1 AN: 180298 AF XY: 0.0000150

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000125

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000972 AC: 10 AN: 1028839 Hom.: 0 Cov.: 41 AF XY: 0.00 AC XY: 0 AN XY: 340195

⚠️ 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: 25647

American (AMR) AF: 0.00 AC: 0 AN: 32043

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17687

East Asian (EAS) AF: 0.00 AC: 0 AN: 27428

South Asian (SAS) AF: 0.00 AC: 0 AN: 48360

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35636

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2962

European-Non Finnish (NFE) AF: 0.0000126 AC: 10 AN: 796526

Other (OTH) AF: 0.00 AC: 0 AN: 42550

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000217325), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000100 AC: 1 AN: 99667 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 25953

African (AFR) AF: 0.00 AC: 0 AN: 27392

American (AMR) AF: 0.00 AC: 0 AN: 9305

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2397

East Asian (EAS) AF: 0.00 AC: 0 AN: 3265

South Asian (SAS) AF: 0.00 AC: 0 AN: 2002

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5099

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.0000208 AC: 1 AN: 48098

Other (OTH) AF: 0.00 AC: 0 AN: 1297

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000836 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-1.0
CADD	Benign	4.8
DANN	Benign	0.53
DEOGEN2	Benign	0.0046	T
FATHMM_MKL	Benign	0.0017	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.00066	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-3.1
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.027
Sift	Benign	0.18	T
Sift4G	Benign	0.10	T
Polyphen		0.69	P
Vest4		0.039
MutPred		0.22		Loss of phosphorylation at S168 (P = 0.0013)
MVP		0.043
MPC		0.25
ClinPred		0.12	T
GERP RS		-1.2
Varity_R		0.091
gMVP		0.0022
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: rs1171793924; hg19: chrX-6451844;