dbSNP rs138128701: VMA21:p.Glu17Asp (chrX-151396890-G-C) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001363810.1(VMA21):c.51G>C(p.Glu17Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00089 in 522,449 control chromosomes in the GnomAD database, including 4 homozygotes. There are 119 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0026 ( 3 hom., 79 hem., cov: 21)

Exomes 𝑓: 0.00043 ( 1 hom. 40 hem. )

Consequence

VMA21
NM_001363810.1 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0860

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0035504699).

BP6

Variant X-151396890-G-C is Benign according to our data. Variant chrX-151396890-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1690444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 3 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363810.1. 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_001363810.1		c.51G>C	p.Glu17Asp	missense	Exon 1 of 3	NP_001350739.1	Q3ZAQ7-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VMA21	ENST00000370361.5	TSL:5	c.51G>C	p.Glu17Asp	missense	Exon 2 of 4	ENSP00000359386.1	Q3ZAQ7-2
ENSG00000287918	ENST00000660681.3		n.248C>G		non_coding_transcript_exon	Exon 1 of 2
ENSG00000287918	ENST00000664935.1		n.129C>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.00256

AC:

283

AN:

110576

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00873

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00132

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:

0.0000379

Gnomad OTH

AF:

0.00135

GnomAD2 exomes

AF:

0.000507

AC:

AN:

102574

AF XY:

0.000348

show subpopulations

Gnomad AFR exome

AF:

0.00842

Gnomad AMR exome

AF:

0.000471

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:

0.000328

GnomAD4 exome

AF:

0.000435

AC:

179

AN:

411828

Hom.:

Cov.:

AF XY:

0.000263

AC XY:

AN XY:

151894

show subpopulations

African (AFR)

AF:

0.0103

AC:

129

AN:

12487

American (AMR)

AF:

0.000444

AC:

AN:

27057

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14653

East Asian (EAS)

AF:

0.00

AC:

AN:

24102

South Asian (SAS)

AF:

0.0000792

AC:

AN:

37863

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36056

Middle Eastern (MID)

AF:

0.00269

AC:

AN:

2979

European-Non Finnish (NFE)

AF:

0.0000428

AC:

AN:

233453

Other (OTH)

AF:

0.000733

AC:

AN:

23178

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

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:

0.00259

AC:

286

AN:

110621

Hom.:

Cov.:

AF XY:

0.00240

AC XY:

AN XY:

32859

show subpopulations

African (AFR)

AF:

0.00881

AC:

268

AN:

30429

American (AMR)

AF:

0.00132

AC:

AN:

10586

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2632

East Asian (EAS)

AF:

0.00

AC:

AN:

3491

South Asian (SAS)

AF:

0.00

AC:

AN:

2466

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5897

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0000379

AC:

AN:

52723

Other (OTH)

AF:

0.00133

AC:

AN:

1502

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.00221

Hom.:

Bravo

AF:

0.00265

ExAC

AF:

0.000163

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

See cases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.91

CADD

Benign

3.1

(source)

DANN

Benign

0.69

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.29

MetaRNN

Benign

0.0036

MetaSVM

Benign

-1.0

PhyloP100

0.086

PROVEAN

Benign

0.11

REVEL

Benign

0.028

Sift

Pathogenic

0.0

Vest4

0.057

MutPred

0.085

Loss of helix (P = 0.079)

MVP

0.29

ClinPred

0.0063

GERP RS

-0.85

PromoterAI

0.019

Neutral

(source)

gMVP

0.072

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over