dbSNP rs753376606: VMA21:p.Gly65Glu (chrX-151397033-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001363810.1(VMA21):c.194G>A(p.Gly65Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 500,328 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G65A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 21)

Exomes 𝑓: 0.000026 ( 0 hom. 6 hem. )

Consequence

VMA21
NM_001363810.1 missense

Scores

Clinical Significance

Not reported in ClinVar

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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07931459).

BS2

High Hemizygotes in GnomAdExome4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VMA21	NM_001363810.1 link	c.194G>A	p.Gly65Glu	missense_variant	Exon 1 of 3		NP_001350739.1
VMA21	NM_001017980.4 link	c.-276G>A		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>A		upstream_gene_variant		1	NM_001017980.4	ENSP00000333255.6		Q3ZAQ7-1

Frequencies

GnomAD3 genomes

AF:

0.0000270

AC:

AN:

111128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000327

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000380

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

84537

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000257

AC:

AN:

389200

Hom.:

Cov.:

AF XY:

0.0000438

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:

0.00

AC:

AN:

23526

South Asian (SAS)

AF:

0.0000274

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:

0.0000401

AC:

AN:

224285

Other (OTH)

AF:

0.00

AC:

AN:

22272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.0000270

AC:

AN:

111128

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33466

show subpopulations

African (AFR)

AF:

0.0000327

AC:

AN:

30584

American (AMR)

AF:

0.00

AC:

AN:

10692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2639

East Asian (EAS)

AF:

0.00

AC:

AN:

3475

South Asian (SAS)

AF:

0.00

AC:

AN:

2674

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5950

Middle Eastern (MID)

AF:

0.00

AC:

AN:

233

European-Non Finnish (NFE)

AF:

0.0000380

AC:

AN:

52698

Other (OTH)

AF:

0.00

AC:

AN:

1502

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-1.1

CADD

Benign

2.9

(source)

DANN

Benign

0.87

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.39

M_CAP

Benign

0.046

MetaRNN

Benign

0.079

MetaSVM

Benign

-1.0

PhyloP100

-0.98

PROVEAN

Benign

-0.24

REVEL

Benign

0.042

Sift

Uncertain

0.0060

Sift4G

Benign

0.24

Vest4

0.041

MutPred

0.16

Loss of loop (P = 0.0112);

MVP

0.38

ClinPred

0.15

GERP RS

-0.93

PromoterAI

-0.071

Neutral

(source)

gMVP

0.29

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over