rs201325403

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001692.4(ATP6V1B1):c.362T>A(p.Met121Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000264 in 1,590,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

ATP6V1B1
NM_001692.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 7.99

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:

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 Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.921

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP6V1B1	NM_001692.4 linkuse as main transcript	c.362T>A	p.Met121Lys	missense_variant	4/14	ENST00000234396.10
ATP6V1B1	XM_011532907.3 linkuse as main transcript	c.482T>A	p.Met161Lys	missense_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6V1B1	ENST00000234396.10 linkuse as main transcript	c.362T>A	p.Met121Lys	missense_variant	4/14	1	NM_001692.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151338

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251328

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000285

AC:

AN:

1439660

Hom.:

Cov.:

AF XY:

0.0000279

AC XY:

AN XY:

717196

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000449

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000320

Gnomad4 OTH exome

AF:

0.0000673

GnomAD4 genome

AF:

0.00000661

AC:

AN:

151338

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73918

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000496

Hom.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 02, 2017

The p.Met121Lys variant in ATP6V1B1 has not been previously reported in individu als with hearing loss, but has been identified in 8/126596 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; d bSNP rs201325403). Although this variant has been seen in the general population , its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis suggest that the p.Met121Lys variant may impact the protein, though this information is not predictive enough to dete rmine pathogenicity. In summary, the clinical significance of the p.Met121Lys va riant is uncertain. ACMG/AMP Criteria applied: PM2, PP3 (Richards 2015). -

Renal tubular acidosis with progressive nerve deafness

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Oct 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.39

Cadd

Pathogenic

Dann

Uncertain

0.97

DEOGEN2

Uncertain

0.79

D;.;.

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Pathogenic

0.48

MetaRNN

Pathogenic

0.92

D;D;D

MetaSVM

Uncertain

0.76

MutationAssessor

Pathogenic

4.2

H;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-4.9

D;.;D

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;.;D

Sift4G

Pathogenic

0.0

D;.;D

Polyphen

0.99

D;.;D

Vest4

0.97

MVP

0.98

MPC

0.70

ClinPred

0.99

GERP RS

4.6

Varity_R

0.95

gMVP

0.98

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