rs140025330

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001017980.4(VMA21):c.166G>A(p.Ala56Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000448 in 1,204,401 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., 4 hem., cov: 22)

Exomes 𝑓: 0.000029 ( 0 hom. 7 hem. )

Consequence

VMA21
NM_001017980.4 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.31

Publications

2 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.029051095).

BS2

High Hemizygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VMA21	NM_001017980.4 link	c.166G>A	p.Ala56Thr	missense_variant, splice_region_variant	Exon 3 of 3	ENST00000330374.7	NP_001017980.1
VMA21	NM_001363810.1 link	c.331G>A	p.Ala111Thr	missense_variant, splice_region_variant	Exon 3 of 3		NP_001350739.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
VMA21	ENST00000330374.7 link	c.166G>A	p.Ala56Thr	missense_variant, splice_region_variant	Exon 3 of 3	1	NM_001017980.4	ENSP00000333255.6
VMA21	ENST00000370361.5 link	c.331G>A	p.Ala111Thr	missense_variant, splice_region_variant	Exon 4 of 4	5		ENSP00000359386.1
VMA21	ENST00000477649.1 link	n.246G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

107839

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000613

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000289

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000573

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000716

AC:

AN:

181559

AF XY:

0.0000302

show subpopulations

Gnomad AFR exome

AF:

0.000914

Gnomad AMR exome

AF:

0.0000366

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:

0.0000292

AC:

AN:

1096562

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

362168

show subpopulations

African (AFR)

AF:

0.000949

AC:

AN:

26354

American (AMR)

AF:

0.0000569

AC:

AN:

35147

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19344

East Asian (EAS)

AF:

0.00

AC:

AN:

30186

South Asian (SAS)

AF:

0.00

AC:

AN:

53672

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40255

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4131

European-Non Finnish (NFE)

AF:

0.00000357

AC:

AN:

841435

Other (OTH)

AF:

0.0000434

AC:

AN:

46038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

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:

0.000204

AC:

AN:

107839

Hom.:

Cov.:

AF XY:

0.000131

AC XY:

AN XY:

30561

show subpopulations

African (AFR)

AF:

0.000613

AC:

AN:

29366

American (AMR)

AF:

0.00

AC:

AN:

10014

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2607

East Asian (EAS)

AF:

0.000289

AC:

AN:

3463

South Asian (SAS)

AF:

0.00

AC:

AN:

2440

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5269

Middle Eastern (MID)

AF:

0.00

AC:

AN:

233

European-Non Finnish (NFE)

AF:

0.0000573

AC:

AN:

52322

Other (OTH)

AF:

0.00

AC:

AN:

1446

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.0000434

Hom.:

Bravo

AF:

0.000223

ESP6500AA

AF:

0.000782

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jan 30, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.166G>A (p.A56T) alteration is located in exon 3 (coding exon 3) of the VMA21 gene. This alteration results from a G to A substitution at nucleotide position 166, causing the alanine (A) at amino acid position 56 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

X-linked myopathy with excessive autophagy

Uncertain:1

Aug 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 56 of the VMA21 protein (p.Ala56Thr). This variant is present in population databases (rs140025330, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with VMA21-related conditions. ClinVar contains an entry for this variant (Variation ID: 570316). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0010

.;T

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.025

MetaRNN

Benign

0.029

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.71

.;N

PhyloP100

1.3

PrimateAI

Benign

0.39

PROVEAN

Benign

0.11

N;N

REVEL

Benign

0.048

Sift

Benign

0.33

T;T

Sift4G

Benign

0.50

T;T

Polyphen

0.0

.;B

Vest4

0.16

MVP

0.37

MPC

0.75

ClinPred

0.029

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.075

gMVP

0.76

Mutation Taster

=77/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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