Genetic Variant VCX3A:p.Val140Met (chrX-6533888-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_016379.4(VCX3A):c.418G>A(p.Val140Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0070 ( 0 hom., 0 hem., cov: 13)

Exomes 𝑓: 0.0015 ( 0 hom. 15 hem. )

Failed GnomAD Quality Control

Consequence

VCX3A
NM_016379.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -4.36

Publications

14 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0084787905).

BP6

Variant X-6533888-C-T is Benign according to our data. Variant chrX-6533888-C-T is described in ClinVar as Benign. ClinVar VariationId is 218736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.418G>A	p.Val140Met	missense	Exon 3 of 3	NP_057463.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VCX3A	ENST00000381089.7	TSL:1 MANE Select	c.418G>A	p.Val140Met	missense	Exon 3 of 3	ENSP00000370479.3	Q9NNX9
VCX3A	ENST00000898738.1		c.418G>A	p.Val140Met	missense	Exon 2 of 2	ENSP00000568797.1
VCX3A	ENST00000398729.1	TSL:5	c.358G>A	p.Val120Met	missense splice_region	Exon 4 of 4	ENSP00000381713.1	E7ESE9

Frequencies

GnomAD3 genomes

AF:

0.00696

AC:

462

AN:

66340

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0136

Gnomad AMI

AF:

0.00198

Gnomad AMR

AF:

0.00700

Gnomad ASJ

AF:

0.00463

Gnomad EAS

AF:

0.00678

Gnomad SAS

AF:

0.00156

Gnomad FIN

AF:

0.00338

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00549

Gnomad OTH

AF:

0.0111

GnomAD2 exomes

AF:

0.0432

AC:

1218

AN:

28216

AF XY:

0.00114

show subpopulations

Gnomad AFR exome

AF:

0.0898

Gnomad AMR exome

AF:

0.00665

Gnomad ASJ exome

AF:

0.0233

Gnomad EAS exome

AF:

0.0300

Gnomad FIN exome

AF:

0.157

Gnomad NFE exome

AF:

0.0359

Gnomad OTH exome

AF:

0.0181

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00154

AC:

598

AN:

388549

Hom.:

Cov.:

AF XY:

0.000101

AC XY:

AN XY:

149135

show subpopulations

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

African (AFR)

AF:

0.00308

AC:

AN:

7136

American (AMR)

AF:

0.00108

AC:

AN:

12975

Ashkenazi Jewish (ASJ)

AF:

0.00131

AC:

AN:

9140

East Asian (EAS)

AF:

0.00178

AC:

AN:

17981

South Asian (SAS)

AF:

0.000983

AC:

AN:

25432

European-Finnish (FIN)

AF:

0.00371

AC:

AN:

25904

Middle Eastern (MID)

AF:

0.00232

AC:

AN:

1293

European-Non Finnish (NFE)

AF:

0.00137

AC:

367

AN:

268843

Other (OTH)

AF:

0.00136

AC:

AN:

19845

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.335

Heterozygous variant carriers

112

149

186

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00700

AC:

464

AN:

66319

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

14779

show subpopulations

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

African (AFR)

AF:

0.0136

AC:

163

AN:

11952

American (AMR)

AF:

0.00713

AC:

AN:

7152

Ashkenazi Jewish (ASJ)

AF:

0.00463

AC:

AN:

1726

East Asian (EAS)

AF:

0.00680

AC:

AN:

2058

South Asian (SAS)

AF:

0.00158

AC:

AN:

1269

European-Finnish (FIN)

AF:

0.00338

AC:

AN:

3841

Middle Eastern (MID)

AF:

0.00

AC:

AN:

130

European-Non Finnish (NFE)

AF:

0.00549

AC:

202

AN:

36790

Other (OTH)

AF:

0.0111

AC:

AN:

897

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.299

Heterozygous variant carriers

115

153

191

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0240

AC:

950

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.85

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.66

(source)

DANN

Benign

0.62

DEOGEN2

Benign

0.0069

FATHMM_MKL

Benign

0.00038

LIST_S2

Benign

0.51

MetaRNN

Benign

0.0085

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.55

PhyloP100

-4.4

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.5

REVEL

Benign

0.014

Sift

Benign

0.098

Sift4G

Benign

0.13

Polyphen

0.28

Vest4

0.047

MPC

0.27

ClinPred

0.0020

Varity_R

0.19

gMVP

0.0044

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over