Genetic Variant VMA21:p.Arg3His (chrX-151397316-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001017980.4(VMA21):c.8G>A(p.Arg3His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000477 in 1,047,472 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 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. R3L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 0.0000048 ( 0 hom. 1 hem. )

Consequence

VMA21
NM_001017980.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.40

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: Orphanet, Labcorp Genetics (formerly Invitae)

VMA21 links:

ENSG00000287918 (HGNC:):

ENSG00000287918 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16950503).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001017980.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VMA21	NM_001017980.4	MANE Select	c.8G>A	p.Arg3His	missense	Exon 1 of 3	NP_001017980.1	Q3ZAQ7-1
	VMA21	NM_001363810.1		c.218+259G>A		intron	N/A	NP_001350739.1	Q3ZAQ7-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VMA21	ENST00000330374.7	TSL:1 MANE Select	c.8G>A	p.Arg3His	missense	Exon 1 of 3	ENSP00000333255.6	Q3ZAQ7-1
VMA21	ENST00000932111.1		c.8G>A	p.Arg3His	missense	Exon 1 of 3	ENSP00000602170.1
VMA21	ENST00000370361.5	TSL:5	c.218+259G>A		intron	N/A	ENSP00000359386.1	Q3ZAQ7-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000998

AC:

AN:

100185

AF XY:

0.0000282

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000477

AC:

AN:

1047472

Hom.:

Cov.:

AF XY:

0.00000292

AC XY:

AN XY:

342012

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24882

American (AMR)

AF:

0.00

AC:

AN:

27905

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18630

East Asian (EAS)

AF:

0.00

AC:

AN:

27118

South Asian (SAS)

AF:

0.0000603

AC:

AN:

49772

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31864

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3933

European-Non Finnish (NFE)

AF:

0.00000244

AC:

AN:

819103

Other (OTH)

AF:

0.00

AC:

AN:

44265

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

0.0010

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0063

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.71

M_CAP

Uncertain

0.093

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.90

PhyloP100

3.4

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.98

REVEL

Benign

0.15

Sift

Benign

0.038

Sift4G

Benign

0.071

Polyphen

0.97

Vest4

0.29

MutPred

0.22

Gain of methylation at K6 (P = 0.1443)

MVP

0.36

MPC

1.0

ClinPred

0.36

GERP RS

5.2

PromoterAI

0.11

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.12

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over