Genetic Variant ATP4A:p.Val971Leu (chr19-35551086-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000704.3(ATP4A):c.2911G>C(p.Val971Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,459,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V971M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

ATP4A
NM_000704.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.510

Publications

5 publications found

Variant links:

Genes affected

ATP4A (HGNC:819): (ATPase H+/K+ transporting subunit alpha) 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 a catalytic alpha subunit of the gastric H+, K+-ATPase. [provided by RefSeq, Jul 2008]

ATP4A Gene-Disease associations (from GenCC):

familial gastric type 1 neuroendocrine tumor
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
gastric neuroendocrine neoplasm
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ATP4A links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2260687).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000704.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP4A	NM_000704.3	MANE Select	c.2911G>C	p.Val971Leu	missense	Exon 20 of 22	NP_000695.2	P20648

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP4A	ENST00000262623.4	TSL:1 MANE Select	c.2911G>C	p.Val971Leu	missense	Exon 20 of 22	ENSP00000262623.2	P20648
	ATP4A	ENST00000592131.5	TSL:2	n.1304G>C		non_coding_transcript_exon	Exon 8 of 10

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000407

AC:

AN:

245828

AF XY:

0.00000752

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000902

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1459656

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725940

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33426

American (AMR)

AF:

0.00

AC:

AN:

44450

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26082

East Asian (EAS)

AF:

0.00

AC:

AN:

39612

South Asian (SAS)

AF:

0.00

AC:

AN:

85812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53264

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1110970

Other (OTH)

AF:

0.00

AC:

AN:

60280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.34

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.85

M_CAP

Benign

0.065

MetaRNN

Benign

0.23

MetaSVM

Uncertain

-0.071

MutationAssessor

Benign

0.14

PhyloP100

0.51

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.060

REVEL

Uncertain

0.43

Sift

Benign

0.45

Sift4G

Benign

0.69

Polyphen

0.0020

Vest4

0.36

MutPred

0.45

Loss of catalytic residue at V971 (P = 0.1506)

MVP

0.91

MPC

0.79

ClinPred

0.37

GERP RS

4.9

Varity_R

0.14

gMVP

0.62

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over