NM_001363810.1:c.194G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 11/14 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

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

X-linked myopathy with excessive autophagy
Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

VMA21 links:

ENSG00000287918 (HGNC:):

ENSG00000287918 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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.:

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

GnomAD2 exomes

AF:

0.000781

AC:

AN:

84537

AF XY:

0.000608

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 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

African (AFR)

AF:

0.00

AC:

AN:

11910

American (AMR)

AF:

0.00

AC:

AN:

25802

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14203

East Asian (EAS)

AF:

0.00769

AC:

181

AN:

23524

South Asian (SAS)

AF:

0.00

AC:

AN:

36515

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28567

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2120

European-Non Finnish (NFE)

AF:

0.00000446

AC:

AN:

224285

Other (OTH)

AF:

0.000449

AC:

AN:

22272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.523

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000324

AC:

AN:

111174

Hom.:

Cov.:

AF XY:

0.000388

AC XY:

AN XY:

33520

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30649

American (AMR)

AF:

0.00

AC:

AN:

10705

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2639

East Asian (EAS)

AF:

0.00982

AC:

AN:

3462

South Asian (SAS)

AF:

0.00

AC:

AN:

2664

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5950

Middle Eastern (MID)

AF:

0.00

AC:

AN:

213

European-Non Finnish (NFE)

AF:

0.0000190

AC:

AN:

52690

Other (OTH)

AF:

0.000657

AC:

AN:

1521

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

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:

0.0000869

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

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.93

BayesDel_noAF

Benign

-1.1

CADD

Benign

2.3

(source)

DANN

Benign

0.71

FATHMM_MKL

Benign

0.067

LIST_S2

Benign

0.38

MetaRNN

Benign

0.0045

MetaSVM

Benign

-1.0

PhyloP100

-0.98

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

PromoterAI

0.031

Neutral

(source)

gMVP

0.35

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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