dbSNP rs1026435: ATP6V0A4:p.Phe554Phe (chr7-138734165-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_020632.3(ATP6V0A4):c.1662C>T(p.Phe554Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.716 in 1,612,318 control chromosomes in the GnomAD database, including 414,815 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.70 ( 37579 hom., cov: 31)

Exomes 𝑓: 0.72 ( 377236 hom. )

Consequence

ATP6V0A4
NM_020632.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.143

Publications

25 publications found

Variant links:

Genes affected

ATP6V0A4 (HGNC:866): (ATPase H+ transporting V0 subunit a4) This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of intracellular compartments of eukaryotic cells. V-ATPase dependent acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain. The V1 domain consists of three A and three B subunits, two G subunits plus the C, D, E, F, and H subunits. The V1 domain contains the ATP catalytic site. The V0 domain consists of five different subunits: a, c, c', c'', and d. This gene is one of four genes in man and mouse that encode different isoforms of the a subunit. Alternatively spliced transcript variants encoding the same protein have been described. Mutations in this gene are associated with renal tubular acidosis associated with preserved hearing. [provided by RefSeq, Jul 2008]

ATP6V0A4 Gene-Disease associations (from GenCC):

renal tubular acidosis, distal, 3, with or without sensorineural hearing loss
Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
autosomal recessive distal renal tubular acidosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ATP6V0A4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 7-138734165-G-A is Benign according to our data. Variant chr7-138734165-G-A is described in ClinVar as Benign. ClinVar VariationId is 261342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.143 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.782 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020632.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ATP6V0A4	NM_020632.3	MANE Select	c.1662C>T	p.Phe554Phe	synonymous	Exon 16 of 22	NP_065683.2
ATP6V0A4	NM_130840.3		c.1662C>T	p.Phe554Phe	synonymous	Exon 15 of 21	NP_570855.2
ATP6V0A4	NM_130841.3		c.1662C>T	p.Phe554Phe	synonymous	Exon 15 of 21	NP_570856.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ATP6V0A4	ENST00000310018.7	TSL:1 MANE Select	c.1662C>T	p.Phe554Phe	synonymous	Exon 16 of 22	ENSP00000308122.2
ATP6V0A4	ENST00000353492.4	TSL:1	c.1662C>T	p.Phe554Phe	synonymous	Exon 15 of 21	ENSP00000253856.6
ATP6V0A4	ENST00000393054.5	TSL:5	c.1662C>T	p.Phe554Phe	synonymous	Exon 15 of 21	ENSP00000376774.1

Frequencies

GnomAD3 genomes

AF:

0.700

AC:

106372

AN:

151886

Hom.:

37569

Cov.:

show subpopulations

Gnomad AFR

AF:

0.620

Gnomad AMI

AF:

0.774

Gnomad AMR

AF:

0.759

Gnomad ASJ

AF:

0.670

Gnomad EAS

AF:

0.802

Gnomad SAS

AF:

0.721

Gnomad FIN

AF:

0.771

Gnomad MID

AF:

0.687

Gnomad NFE

AF:

0.717

Gnomad OTH

AF:

0.676

GnomAD2 exomes

AF:

0.734

AC:

184541

AN:

251354

AF XY:

0.731

show subpopulations

Gnomad AFR exome

AF:

0.611

Gnomad AMR exome

AF:

0.826

Gnomad ASJ exome

AF:

0.682

Gnomad EAS exome

AF:

0.812

Gnomad FIN exome

AF:

0.765

Gnomad NFE exome

AF:

0.714

Gnomad OTH exome

AF:

0.729

GnomAD4 exome

AF:

0.718

AC:

1048162

AN:

1460314

Hom.:

377236

Cov.:

AF XY:

0.718

AC XY:

521352

AN XY:

726514

show subpopulations

African (AFR)

AF:

0.616

AC:

20595

AN:

33430

American (AMR)

AF:

0.818

AC:

36581

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.675

AC:

17631

AN:

26106

East Asian (EAS)

AF:

0.790

AC:

31344

AN:

39672

South Asian (SAS)

AF:

0.720

AC:

62046

AN:

86228

European-Finnish (FIN)

AF:

0.763

AC:

40751

AN:

53374

Middle Eastern (MID)

AF:

0.672

AC:

3873

AN:

5764

European-Non Finnish (NFE)

AF:

0.713

AC:

792246

AN:

1110712

Other (OTH)

AF:

0.715

AC:

43095

AN:

60312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

16741

33483

50224

66966

83707

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19824

39648

59472

79296

99120

<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:

0.700

AC:

106427

AN:

152004

Hom.:

37579

Cov.:

AF XY:

0.703

AC XY:

52208

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.619

AC:

25665

AN:

41442

American (AMR)

AF:

0.760

AC:

11586

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.670

AC:

2325

AN:

3472

East Asian (EAS)

AF:

0.802

AC:

4134

AN:

5154

South Asian (SAS)

AF:

0.721

AC:

3474

AN:

4820

European-Finnish (FIN)

AF:

0.771

AC:

8157

AN:

10580

Middle Eastern (MID)

AF:

0.697

AC:

205

AN:

294

European-Non Finnish (NFE)

AF:

0.717

AC:

48757

AN:

67966

Other (OTH)

AF:

0.672

AC:

1420

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1654

3307

4961

6614

8268

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

832

1664

2496

3328

4160

<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:

0.710

Hom.:

96713

Bravo

AF:

0.697

Asia WGS

AF:

0.732

AC:

2546

AN:

3478

EpiCase

AF:

0.715

EpiControl

AF:

0.724

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Autosomal recessive distal renal tubular acidosis (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.28

(source)

DANN

Benign

0.48

PhyloP100

-0.14

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over