NM_001692.4:c.481G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_001692.4(ATP6V1B1):c.481G>A(p.Glu161Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.025 in 1,614,138 control chromosomes in the GnomAD database, including 794 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 65 hom., cov: 32)

Exomes 𝑓: 0.025 ( 729 hom. )

Consequence

ATP6V1B1
NM_001692.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:12

Conservation

PhyloP100: 9.99

Variant links:

Genes affected

ATP6V1B1 (HGNC:853): (ATPase H+ transporting V1 subunit B1) This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. V-ATPase dependent organelle 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. Additional isoforms of many of the V1 and V0 subunit proteins are encoded by multiple genes or alternatively spliced transcript variants. This encoded protein is one of two V1 domain B subunit isoforms and is found in the kidney. Mutations in this gene cause distal renal tubular acidosis associated with sensorineural deafness. [provided by RefSeq, Jul 2008]

ATP6V1B1 links:

ENSG00000258881 (HGNC:):

ENSG00000258881 links:

VAX2 (HGNC:12661): (ventral anterior homeobox 2) This gene encodes a homeobox protein and is almost exclusively expressed in the ventral portion of the retina during development. In mouse studies, this gene was found to be required for the correct formation of the optic fissure and other aspects of retinal development. [provided by RefSeq, Sep 2008]

VAX2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 2-70959974-G-A is Benign according to our data. Variant chr2-70959974-G-A is described in ClinVar as [Benign]. Clinvar id is 44229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-70959974-G-A is described in Lovd as [Benign]. Variant chr2-70959974-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0585 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6V1B1	NM_001692.4 link	c.481G>A	p.Glu161Lys	missense_variant	Exon 6 of 14	ENST00000234396.10	NP_001683.2	P15313
ATP6V1B1	XM_011532907.3 link	c.601G>A	p.Glu201Lys	missense_variant	Exon 5 of 13		XP_011531209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6V1B1	ENST00000234396.10 link	c.481G>A	p.Glu161Lys	missense_variant	Exon 6 of 14	1	NM_001692.4	ENSP00000234396.4		P15313
ENSG00000258881	ENST00000606025.5 link	c.476-17541C>T		intron_variant	Intron 5 of 5	5		ENSP00000475641.1		U3KQ87

Frequencies

GnomAD3 genomes

AF:

0.0260

AC:

3957

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0262

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0184

Gnomad ASJ

AF:

0.0553

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0635

Gnomad FIN

AF:

0.0491

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0217

Gnomad OTH

AF:

0.0339

GnomAD3 exomes

AF:

0.0300

AC:

7535

AN:

251352

Hom.:

191

AF XY:

0.0334

AC XY:

4536

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.0258

Gnomad AMR exome

AF:

0.0125

Gnomad ASJ exome

AF:

0.0586

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0692

Gnomad FIN exome

AF:

0.0525

Gnomad NFE exome

AF:

0.0230

Gnomad OTH exome

AF:

0.0347

GnomAD4 exome

AF:

0.0249

AC:

36452

AN:

1461864

Hom.:

729

Cov.:

AF XY:

0.0269

AC XY:

19550

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0274

Gnomad4 AMR exome

AF:

0.0136

Gnomad4 ASJ exome

AF:

0.0589

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.0712

Gnomad4 FIN exome

AF:

0.0528

Gnomad4 NFE exome

AF:

0.0201

Gnomad4 OTH exome

AF:

0.0284

GnomAD4 genome

AF:

0.0260

AC:

3960

AN:

152274

Hom.:

Cov.:

AF XY:

0.0275

AC XY:

2050

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0261

Gnomad4 AMR

AF:

0.0184

Gnomad4 ASJ

AF:

0.0553

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.0644

Gnomad4 FIN

AF:

0.0491

Gnomad4 NFE

AF:

0.0217

Gnomad4 OTH

AF:

0.0331

Alfa

AF:

0.0239

Hom.:

Bravo

AF:

0.0222

TwinsUK

AF:

0.0221

AC:

ALSPAC

AF:

0.0202

AC:

ESP6500AA

AF:

0.0259

AC:

114

ESP6500EA

AF:

0.0219

AC:

188

ExAC

AF:

0.0306

AC:

3714

Asia WGS

AF:

0.0240

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Renal tubular acidosis with progressive nerve deafness

Pathogenic:1Benign:4

Mar 06, 2017

Counsyl

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 07, 2022

Laboratory of Cyto-molecular Genetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:5

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Glu161Lys in Exon 06 of ATP6V1B1: This variant is not expected to have clinical significance because it has been identified in 2.4% (90/3738) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs114234874). -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 06, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jan 20, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 15, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATP6V1B1 c.481G>A (p.Glu161Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.03 in 251352 control chromosomes in the gnomAD database, including 191 homozygotes. The observed variant frequency is approximately 27-fold of the estimated maximal expected allele frequency for a pathogenic variant in ATP6V1B1 causing Renal Tubular Acidosis With Progressive Nerve Deafness phenotype (0.0011), strongly suggesting that the variant is benign. To our knowledge, no penetrant association of c.481G>A with Renal Tubular Acidosis With Progressive Nerve Deafness has been reported. Nine submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. The majority classified the variant as benign (n=8), and one classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:3

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;.;.

Eigen

Benign

0.073

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D

MetaRNN

Benign

0.0061

T;T;T

MetaSVM

Benign

-0.64

MutationAssessor

Benign

0.47

N;.;.

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.9

N;.;N

REVEL

Benign

0.24

Sift

Benign

0.14

T;.;T

Sift4G

Benign

0.20

T;.;T

Polyphen

0.0010

B;.;B

Vest4

0.46

MPC

0.35

ClinPred

0.024

GERP RS

4.5

Varity_R

0.28

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.42

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.42

Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over