chrX-151397323-T-G

Position:

chrX-151397323-T-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001017980.4(VMA21):c.15T>G(p.Asp5Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000434 in 1,161,102 control chromosomes in the GnomAD database, including 1 homozygotes. There are 182 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., 7 hem., cov: 24)

Exomes 𝑓: 0.00044 ( 1 hom. 175 hem. )

Consequence

VMA21
NM_001017980.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 0.262

Variant links:

Genes affected

VMA21 (HGNC:22082): (vacuolar ATPase assembly factor VMA21) This gene encodes a chaperone for assembly of lysosomal vacuolar ATPase.[provided by RefSeq, Jul 2012]

VMA21 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016320378).

BP6

Variant X-151397323-T-G is Benign according to our data. Variant chrX-151397323-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 382097.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.

BS2

High Hemizygotes in GnomAd4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VMA21	NM_001017980.4 linkuse as main transcript	c.15T>G	p.Asp5Glu	missense_variant	1/3	ENST00000330374.7
VMA21	NM_001363810.1 linkuse as main transcript	c.218+266T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VMA21	ENST00000330374.7 linkuse as main transcript	c.15T>G	p.Asp5Glu	missense_variant	1/3	1	NM_001017980.4	P1	Q3ZAQ7-1
VMA21	ENST00000370361.5 linkuse as main transcript	c.218+266T>G		intron_variant		5			Q3ZAQ7-2
VMA21	ENST00000477649.1 linkuse as main transcript	n.133+676T>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000354

AC:

AN:

113102

Hom.:

Cov.:

AF XY:

0.000198

AC XY:

AN XY:

35266

show subpopulations

Gnomad AFR

AF:

0.0000320

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000827

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000563

Gnomad SAS

AF:

0.00143

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000432

Gnomad OTH

AF:

0.000653

GnomAD3 exomes

AF:

0.000426

AC:

AN:

100939

Hom.:

AF XY:

0.000618

AC XY:

AN XY:

35601

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000417

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000128

Gnomad SAS exome

AF:

0.00166

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000288

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000443

AC:

464

AN:

1048000

Hom.:

Cov.:

AF XY:

0.000511

AC XY:

175

AN XY:

342220

show subpopulations

Gnomad4 AFR exome

AF:

0.0000402

Gnomad4 AMR exome

AF:

0.000465

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000369

Gnomad4 SAS exome

AF:

0.00197

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000385

Gnomad4 OTH exome

AF:

0.000700

GnomAD4 genome

AF:

0.000354

AC:

AN:

113102

Hom.:

Cov.:

AF XY:

0.000198

AC XY:

AN XY:

35266

show subpopulations

Gnomad4 AFR

AF:

0.0000320

Gnomad4 AMR

AF:

0.000827

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000563

Gnomad4 SAS

AF:

0.00143

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000432

Gnomad4 OTH

AF:

0.000653

Alfa

AF:

0.000260

Hom.:

Bravo

AF:

0.000423

ExAC

AF:

0.000189

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2022

The c.15T>G (p.D5E) alteration is located in exon 1 (coding exon 1) of the VMA21 gene. This alteration results from a T to G substitution at nucleotide position 15, causing the aspartic acid (D) at amino acid position 5 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 22, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

VMA21-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 15, 2020

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). -

X-linked myopathy with excessive autophagy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 20, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2024

VMA21: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.0027

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.56

M_CAP

Benign

0.052

MetaRNN

Benign

0.016

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

MutationTaster

Benign

1.0

D;N

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.52

REVEL

Benign

0.029

Sift

Benign

0.28

Sift4G

Benign

0.47

Polyphen

0.0010

Vest4

0.058

MutPred

0.26

Gain of methylation at K6 (P = 0.08);

MVP

0.068

MPC

0.73

ClinPred

0.016

GERP RS

-0.92

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.059

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over