Genetic Variant VMA21:p.Gly65Ala (chrX-151397033-G-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001363810.1(VMA21):c.194G>C(p.Gly65Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000456 in 500,372 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 80 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 9/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., 13 hem., cov: 21)

Exomes 𝑓: 0.00049 ( 0 hom. 67 hem. )

Consequence

VMA21
NM_001363810.1 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: -0.984

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:

ENSG00000287918 (HGNC:):

ENSG00000287918 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004472047).

BP6

Variant X-151397033-G-C is Benign according to our data. Variant chrX-151397033-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3045664.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd4 at 13 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VMA21	NM_001363810.1 link	c.194G>C	p.Gly65Ala	missense_variant	Exon 1 of 3		NP_001350739.1
VMA21	NM_001017980.4 link	c.-276G>C		upstream_gene_variant		ENST00000330374.7	NP_001017980.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VMA21	ENST00000330374.7 link	c.-276G>C		upstream_gene_variant		1	NM_001017980.4	ENSP00000333255.6		Q3ZAQ7-1

Frequencies

GnomAD3 genomes

AF:

0.000324

AC:

AN:

111127

Hom.:

Cov.:

AF XY:

0.000388

AC XY:

AN XY:

33465

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00979

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000190

Gnomad OTH

AF:

0.000666

GnomAD3 exomes

AF:

0.000781

AC:

AN:

84537

Hom.:

AF XY:

0.000608

AC XY:

AN XY:

26317

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00977

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000773

GnomAD4 exome

AF:

0.000493

AC:

192

AN:

389198

Hom.:

Cov.:

AF XY:

0.000489

AC XY:

AN XY:

136978

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00769

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000446

Gnomad4 OTH exome

AF:

0.000449

GnomAD4 genome

AF:

0.000324

AC:

AN:

111174

Hom.:

Cov.:

AF XY:

0.000388

AC XY:

AN XY:

33520

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00982

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000190

Gnomad4 OTH

AF:

0.000657

Alfa

AF:

0.0000869

Hom.:

Bravo

AF:

0.000419

ExAC

AF:

0.000215

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

VMA21-related disorder

Benign:1

Oct 28, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Benign. Following criteria are met: 0308 - Population frequency for this variant is out of keeping with known incidence of Myopathy, X-linked, with excessive autophagy (MIM#310440). (SB) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.93

BayesDel_noAF

Benign

-1.1

CADD

Benign

2.3

DANN

Benign

0.71

FATHMM_MKL

Benign

0.067

LIST_S2

Benign

0.38

MetaRNN

Benign

0.0045

MetaSVM

Benign

-1.0

PROVEAN

Benign

0.78

REVEL

Benign

0.0060

Sift

Benign

0.16

Sift4G

Benign

1.0

Vest4

0.046

MutPred

0.13

Loss of loop (P = 0.0203);

MVP

0.53

ClinPred

0.0045

GERP RS

-0.93

gMVP

0.35

Splicing

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