Genetic Variant VCX3A:c.*8G>A (chrX-6533737-C-T) – 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.*8G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00581 in 955,576 control chromosomes in the GnomAD database, including 111 homozygotes. There are 1,551 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 0.018 ( 4 hom., 5 hem., cov: 9)

Exomes 𝑓: 0.0052 ( 107 hom. 1546 hem. )

Consequence

VCX3A
NM_016379.4 3_prime_UTR

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: -2.77

Publications

3 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0042508543).

BP6

Variant X-6533737-C-T is Benign according to our data. Variant chrX-6533737-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3058916.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Homozygotes in GnomAd4 at 4 gene

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.*8G>A		3_prime_UTR	Exon 3 of 3	NP_057463.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
VCX3A	ENST00000381089.7	TSL:1 MANE Select	c.*8G>A	3_prime_UTR	Exon 3 of 3	ENSP00000370479.3	Q9NNX9
VCX3A	ENST00000898738.1		c.*8G>A	3_prime_UTR	Exon 2 of 2	ENSP00000568797.1
VCX3A	ENST00000398729.1	TSL:5	c.*8G>A	downstream_gene	N/A	ENSP00000381713.1	E7ESE9

Frequencies

GnomAD3 genomes

AF:

0.0180

AC:

846

AN:

46922

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0586

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0102

Gnomad ASJ

AF:

0.0128

Gnomad EAS

AF:

0.00832

Gnomad SAS

AF:

0.00771

Gnomad FIN

AF:

0.0135

Gnomad MID

AF:

0.0256

Gnomad NFE

AF:

0.0105

Gnomad OTH

AF:

0.0224

GnomAD2 exomes

AF:

0.00109

AC:

188

AN:

172626

AF XY:

0.00100

show subpopulations

Gnomad AFR exome

AF:

0.00348

Gnomad AMR exome

AF:

0.000719

Gnomad ASJ exome

AF:

0.000839

Gnomad EAS exome

AF:

0.00268

Gnomad FIN exome

AF:

0.000574

Gnomad NFE exome

AF:

0.000604

Gnomad OTH exome

AF:

0.000938

GnomAD4 exome

AF:

0.00518

AC:

4709

AN:

908674

Hom.:

107

Cov.:

AF XY:

0.00533

AC XY:

1546

AN XY:

289834

show subpopulations

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

African (AFR)

AF:

0.0138

AC:

211

AN:

15305

American (AMR)

AF:

0.00469

AC:

130

AN:

27701

Ashkenazi Jewish (ASJ)

AF:

0.0140

AC:

192

AN:

13730

East Asian (EAS)

AF:

0.0137

AC:

285

AN:

20834

South Asian (SAS)

AF:

0.0140

AC:

570

AN:

40851

European-Finnish (FIN)

AF:

0.00703

AC:

217

AN:

30870

Middle Eastern (MID)

AF:

0.00839

AC:

AN:

2862

European-Non Finnish (NFE)

AF:

0.00385

AC:

2775

AN:

721230

Other (OTH)

AF:

0.00864

AC:

305

AN:

35291

⚠️ 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: 0.286

Heterozygous variant carriers

288

576

863

1151

1439

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:

0.0180

AC:

844

AN:

46902

Hom.:

Cov.:

AF XY:

0.000381

AC XY:

AN XY:

13120

show subpopulations

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

African (AFR)

AF:

0.0585

AC:

420

AN:

7178

American (AMR)

AF:

0.0102

AC:

AN:

4491

Ashkenazi Jewish (ASJ)

AF:

0.0128

AC:

AN:

1175

East Asian (EAS)

AF:

0.00833

AC:

AN:

2041

South Asian (SAS)

AF:

0.00685

AC:

AN:

1168

European-Finnish (FIN)

AF:

0.0135

AC:

AN:

3262

Middle Eastern (MID)

AF:

0.0189

AC:

AN:

106

European-Non Finnish (NFE)

AF:

0.0105

AC:

278

AN:

26531

Other (OTH)

AF:

0.0224

AC:

AN:

625

⚠️ 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: 0.311

Heterozygous variant carriers

122

184

245

306

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00497

Hom.:

ExAC

AF:

0.00213

AC:

254

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

VCX3A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.90

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.69

(source)

DANN

Benign

0.51

FATHMM_MKL

Benign

0.00042

LIST_S2

Benign

0.19

MetaRNN

Benign

0.0043

PhyloP100

-2.8

Sift4G

Benign

0.45

Vest4

0.15

MVP

0.082

ClinPred

0.0042

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over