Genetic Variant VMA21:p.Asn61Ile (chrX-151404934-A-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001017980.4(VMA21):c.182A>T(p.Asn61Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,937 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 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. N61S) has been classified as Benign.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

VMA21
NM_001017980.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.85

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.34368113).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VMA21	NM_001017980.4 link	c.182A>T	p.Asn61Ile	missense_variant	Exon 3 of 3	ENST00000330374.7	NP_001017980.1
VMA21	NM_001363810.1 link	c.347A>T	p.Asn116Ile	missense_variant	Exon 3 of 3		NP_001350739.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
VMA21	ENST00000330374.7 link	c.182A>T	p.Asn61Ile	missense_variant	Exon 3 of 3	1	NM_001017980.4	ENSP00000333255.6
VMA21	ENST00000370361.5 link	c.347A>T	p.Asn116Ile	missense_variant	Exon 4 of 4	5		ENSP00000359386.1
VMA21	ENST00000477649.1 link	n.262A>T		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1097937

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363311

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26396

American (AMR)

AF:

0.00

AC:

AN:

35196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19382

East Asian (EAS)

AF:

0.00

AC:

AN:

30202

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54118

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40417

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

842011

Other (OTH)

AF:

0.00

AC:

AN:

46081

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.027

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.13

.;T

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.032

MetaRNN

Benign

0.34

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.3

.;M

PhyloP100

2.8

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-4.3

D;D

REVEL

Benign

0.12

Sift

Uncertain

0.019

D;T

Sift4G

Uncertain

0.056

T;T

Polyphen

0.28

.;B

Vest4

0.38

MutPred

0.63

.;Loss of solvent accessibility (P = 0.0058);

MVP

0.80

MPC

1.0

ClinPred

0.93

GERP RS

1.9

Varity_R

0.57

gMVP

0.84

Mutation Taster

=69/31

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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