dbSNP rs77413590: VCX3A:c.*9C>G (chrX-6533736-G-C) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_016379.4(VCX3A):c.*9C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00571 in 966,755 control chromosomes in the GnomAD database, including 110 homozygotes. There are 1,554 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.017 ( 3 hom., 4 hem., cov: 9)

Exomes 𝑓: 0.0051 ( 107 hom. 1550 hem. )

Consequence

VCX3A
NM_016379.4 3_prime_UTR

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.634

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0065132678).

BP6

Variant X-6533736-G-C is Benign according to our data. Variant chrX-6533736-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3060492.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Homozygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCX3A	NM_016379.4 link	c.*9C>G		3_prime_UTR_variant	Exon 3 of 3	ENST00000381089.7	NP_057463.2	Q9NNX9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCX3A	ENST00000381089.7 link	c.*9C>G		3_prime_UTR_variant	Exon 3 of 3	1	NM_016379.4	ENSP00000370479.3		Q9NNX9
VCX3A	ENST00000398729.1 link	c.*9C>G		downstream_gene_variant		5		ENSP00000381713.1		E7ESE9

Frequencies

GnomAD3 genomes

AF:

0.0175

AC:

839

AN:

47931

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0564

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00975

Gnomad ASJ

AF:

0.0110

Gnomad EAS

AF:

0.00820

Gnomad SAS

AF:

0.00758

Gnomad FIN

AF:

0.0136

Gnomad MID

AF:

0.0252

Gnomad NFE

AF:

0.0102

Gnomad OTH

AF:

0.0226

GnomAD2 exomes

AF:

0.00106

AC:

184

AN:

172838

AF XY:

0.00100

show subpopulations

Gnomad AFR exome

AF:

0.00347

Gnomad AMR exome

AF:

0.000718

Gnomad ASJ exome

AF:

0.000840

Gnomad EAS exome

AF:

0.00250

Gnomad FIN exome

AF:

0.000574

Gnomad NFE exome

AF:

0.000578

Gnomad OTH exome

AF:

0.000937

GnomAD4 exome

AF:

0.00510

AC:

4686

AN:

918845

Hom.:

107

Cov.:

AF XY:

0.00529

AC XY:

1550

AN XY:

293137

show subpopulations

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

African (AFR)

AF:

0.0128

AC:

207

AN:

16157

American (AMR)

AF:

0.00467

AC:

130

AN:

27839

Ashkenazi Jewish (ASJ)

AF:

0.0135

AC:

188

AN:

13892

East Asian (EAS)

AF:

0.0134

AC:

280

AN:

20942

South Asian (SAS)

AF:

0.0140

AC:

578

AN:

41213

European-Finnish (FIN)

AF:

0.00698

AC:

217

AN:

31097

Middle Eastern (MID)

AF:

0.00830

AC:

AN:

2893

European-Non Finnish (NFE)

AF:

0.00378

AC:

2757

AN:

729075

Other (OTH)

AF:

0.00853

AC:

305

AN:

35737

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.285

Heterozygous variant carriers

284

568

853

1137

1421

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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

AF:

0.0175

AC:

837

AN:

47910

Hom.:

Cov.:

AF XY:

0.000301

AC XY:

AN XY:

13308

show subpopulations

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

African (AFR)

AF:

0.0563

AC:

417

AN:

7404

American (AMR)

AF:

0.00976

AC:

AN:

4610

Ashkenazi Jewish (ASJ)

AF:

0.0110

AC:

AN:

1185

East Asian (EAS)

AF:

0.00821

AC:

AN:

2070

South Asian (SAS)

AF:

0.00674

AC:

AN:

1187

European-Finnish (FIN)

AF:

0.0136

AC:

AN:

3302

Middle Eastern (MID)

AF:

0.0185

AC:

AN:

108

European-Non Finnish (NFE)

AF:

0.0102

AC:

276

AN:

27085

Other (OTH)

AF:

0.0226

AC:

AN:

620

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.310

Heterozygous variant carriers

125

187

250

312

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00496

Hom.:

ExAC

AF:

0.00213

AC:

254

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

VCX3A-related disorder

Benign:1

May 18, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.87

BayesDel_noAF

Benign

-1.0

CADD

Benign

1.1

(source)

DANN

Benign

0.11

FATHMM_MKL

Benign

0.0014

LIST_S2

Benign

0.23

MetaRNN

Benign

0.0065

PhyloP100

-0.63

Sift4G

Benign

0.47

Vest4

0.16

MVP

0.068

ClinPred

0.0041

GERP RS

-0.22

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over