rs45498896

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001692.4(ATP6V1B1):c.*6C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0167 in 1,607,700 control chromosomes in the GnomAD database, including 310 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 20 hom., cov: 31)

Exomes 𝑓: 0.017 ( 290 hom. )

Consequence

ATP6V1B1
NM_001692.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.0240

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 2-70965127-C-A is Benign according to our data. Variant chr2-70965127-C-A is described in ClinVar as [Benign]. Clinvar id is 44221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0132 (2017/152300) while in subpopulation NFE AF= 0.0198 (1344/68022). AF 95% confidence interval is 0.0189. There are 20 homozygotes in gnomad4. There are 973 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6V1B1	NM_001692.4 linkuse as main transcript	c.*6C>A		3_prime_UTR_variant	14/14	ENST00000234396.10	NP_001683.2	P15313
ATP6V1B1	XM_011532907.3 linkuse as main transcript	c.*6C>A		3_prime_UTR_variant	13/13		XP_011531209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP6V1B1	ENST00000234396.10 linkuse as main transcript	c.*6C>A		3_prime_UTR_variant	14/14	1	NM_001692.4	ENSP00000234396.4		P15313
ENSG00000258881	ENST00000606025.5 linkuse as main transcript	c.476-22694G>T		intron_variant		5		ENSP00000475641.1		U3KQ87

Frequencies

GnomAD3 genomes

AF:

0.0132

AC:

2015

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00326

Gnomad AMI

AF:

0.0362

Gnomad AMR

AF:

0.00805

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.0297

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0197

Gnomad OTH

AF:

0.0134

GnomAD3 exomes

AF:

0.0136

AC:

3278

AN:

241498

Hom.:

AF XY:

0.0139

AC XY:

1837

AN XY:

132468

show subpopulations

Gnomad AFR exome

AF:

0.00290

Gnomad AMR exome

AF:

0.00592

Gnomad ASJ exome

AF:

0.00645

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00413

Gnomad FIN exome

AF:

0.0315

Gnomad NFE exome

AF:

0.0201

Gnomad OTH exome

AF:

0.0114

GnomAD4 exome

AF:

0.0171

AC:

24823

AN:

1455400

Hom.:

290

Cov.:

AF XY:

0.0168

AC XY:

12175

AN XY:

724340

show subpopulations

Gnomad4 AFR exome

AF:

0.00278

Gnomad4 AMR exome

AF:

0.00584

Gnomad4 ASJ exome

AF:

0.00605

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00497

Gnomad4 FIN exome

AF:

0.0280

Gnomad4 NFE exome

AF:

0.0194

Gnomad4 OTH exome

AF:

0.0161

GnomAD4 genome

AF:

0.0132

AC:

2017

AN:

152300

Hom.:

Cov.:

AF XY:

0.0131

AC XY:

973

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00325

Gnomad4 AMR

AF:

0.00804

Gnomad4 ASJ

AF:

0.00634

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00331

Gnomad4 FIN

AF:

0.0297

Gnomad4 NFE

AF:

0.0198

Gnomad4 OTH

AF:

0.0133

Alfa

AF:

0.0144

Hom.:

Bravo

AF:

0.0113

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	*6C>A in Exon 14 of ATP6V1B1: This variant is not expected to have clinical sign ificance because it has been identified in 1.9% (131/6986) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs45498896). -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 14, 2020	- -

Renal tubular acidosis with progressive nerve deafness

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 28, 2019	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 15, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

7.2

DANN

Benign

0.87

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

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