rs140025330

Positions:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000330374.7(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. 13/19 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
ENST00000330374.7 missense, splice_region

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.31

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 -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/exons	MANE	Protein	UniProt
VMA21	NM_001017980.4 linkuse as main transcript	c.166G>A	p.Ala56Thr	missense_variant, splice_region_variant	3/3	ENST00000330374.7	NP_001017980.1
VMA21	NM_001363810.1 linkuse as main transcript	c.331G>A	p.Ala111Thr	missense_variant, splice_region_variant	3/3		NP_001350739.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VMA21	ENST00000330374.7 linkuse as main transcript	c.166G>A	p.Ala56Thr	missense_variant, splice_region_variant	3/3	1	NM_001017980.4	ENSP00000333255	P1	Q3ZAQ7-1
VMA21	ENST00000370361.5 linkuse as main transcript	c.331G>A	p.Ala111Thr	missense_variant, splice_region_variant	4/4	5		ENSP00000359386		Q3ZAQ7-2
VMA21	ENST00000477649.1 linkuse as main transcript	n.246G>A		splice_region_variant, non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

107839

Hom.:

Cov.:

AF XY:

0.000131

AC XY:

AN XY:

30561

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

GnomAD3 exomes

AF:

0.0000716

AC:

AN:

181559

Hom.:

AF XY:

0.0000302

AC XY:

AN XY:

66229

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 SAS 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

Gnomad4 AFR exome

AF:

0.000949

Gnomad4 AMR exome

AF:

0.0000569

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000357

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.000204

AC:

AN:

107839

Hom.:

Cov.:

AF XY:

0.000131

AC XY:

AN XY:

30561

show subpopulations

Gnomad4 AFR

AF:

0.000613

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000289

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000573

Gnomad4 OTH

AF:

0.00

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 30, 2024

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2023

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

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

MutationTaster

Benign

0.91

N;N

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

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

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