chr13-113652931-G-A

Position:

• chr13-113652931-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000335288.5(ATP4B):​c.497C>T​(p.Ala166Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,614,158 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A166E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0080 (16 hom., cov: 33)
  • Exomes 𝑓: 0.00091 (13 hom.)
• Consequence: ATP4B ENST00000335288.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.23

Genes affected

ATP4B (HGNC:820): (ATPase H+/K+ transporting subunit beta) The protein encoded by this gene belongs to a family of P-type cation-transporting ATPases. The gastric H+, K+-ATPase is a heterodimer consisting of a high molecular weight catalytic alpha subunit and a smaller but heavily glycosylated beta subunit. This enzyme is a proton pump that catalyzes the hydrolysis of ATP coupled with the exchange of H(+) and K(+) ions across the plasma membrane. It is also responsible for gastric acid secretion. This gene encodes the beta subunit of the gastric H+, K+-ATPase. [provided by RefSeq, Jul 2008]

GRK1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046102107).
• BP6: Variant 13-113652931-G-A is Benign according to our data. Variant chr13-113652931-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3131645.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00797 (1214/152274) while in subpopulation AFR AF= 0.027 (1123/41542). AF 95% confidence interval is 0.0257. There are 16 homozygotes in gnomad4. There are 575 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP4B	NM_000705.4	c.497C>T	p.Ala166Val	missense_variant	4/7	ENST00000335288.5	NP_000696.1
GRK1	XM_047430493.1	c.-7+4687G>A		intron_variant			XP_047286449.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP4B	ENST00000335288.5	c.497C>T	p.Ala166Val	missense_variant	4/7	1	NM_000705.4	ENSP00000334216	P1

Frequencies

GnomAD3 genomes AF: 0.00795 AC: 1210 AN: 152156 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.0270

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00861

GnomAD3 exomes AF: 0.00236 AC: 593 AN: 251454 Hom.: 5 AF XY: 0.00163 AC XY: 221 AN XY: 135900

Gnomad AFR exome AF: 0.0294

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000912 AC: 1333 AN: 1461884 Hom.: 13 Cov.: 31 AF XY: 0.000815 AC XY: 593 AN XY: 727240

Gnomad4 AFR exome AF: 0.0264

Gnomad4 AMR exome AF: 0.00208

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000141

Gnomad4 OTH exome AF: 0.00253

GnomAD4 genome AF: 0.00797 AC: 1214 AN: 152274 Hom.: 16 Cov.: 33 AF XY: 0.00772 AC XY: 575 AN XY: 74458

Gnomad4 AFR AF: 0.0270

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.000683 Hom.: 1

Bravo AF: 0.00921

ESP6500AA AF: 0.0295 AC: 130

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00259 AC: 315

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 19, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.031
DANN	Benign	0.83
DEOGEN2	Benign	0.063	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.69	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.013
Sift	Benign	0.30	T
Sift4G	Benign	0.29	T
Polyphen		0.0050	B
Vest4		0.10
MVP		0.17
MPC		0.083
ClinPred		0.0077	T
GERP RS		-9.4
Varity_R		0.031
gMVP		0.38

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

Other links and lift over

dbSNP: rs75160036; hg19: chr13-114307246; COSMIC: COSV100090012;