dbSNP rs140025330: VMA21:p.Ala56Thr (chrX-151404918-G-A) – ACMG Classification: Benign (-8 pts)

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: Orphanet, Labcorp Genetics (formerly Invitae)

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

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.166G>A	p.Ala56Thr	missense splice_region	Exon 3 of 3	NP_001017980.1	Q3ZAQ7-1
	VMA21	NM_001363810.1		c.331G>A	p.Ala111Thr	missense splice_region	Exon 3 of 3	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.166G>A	p.Ala56Thr	missense splice_region	Exon 3 of 3	ENSP00000333255.6	Q3ZAQ7-1
VMA21	ENST00000370361.5	TSL:5	c.331G>A	p.Ala111Thr	missense splice_region	Exon 4 of 4	ENSP00000359386.1	Q3ZAQ7-2
VMA21	ENST00000932111.1		c.157G>A	p.Ala53Thr	missense splice_region	Exon 3 of 3	ENSP00000602170.1

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

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

X-linked myopathy with excessive autophagy (1)

Computational scores

Source: dbNSFP v4.9

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

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.82

M_CAP

Benign

0.025

MetaRNN

Benign

0.029

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.71

PhyloP100

1.3

PrimateAI

Benign

0.39

PROVEAN

Benign

0.11

REVEL

Benign

0.048

Sift

Benign

0.33

Sift4G

Benign

0.50

Polyphen

0.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over