19-35555537-G-A

Variant names:

Variant summary

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

The NM_000704.3(ATP4A):c.2060C>T(p.Ser687Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000119 in 1,601,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S687T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

ATP4A
NM_000704.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.64

Publications

1 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:

Genome browser will be placed here

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=0.24722826).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP4A	NM_000704.3 link	c.2060C>T	p.Ser687Leu	missense_variant	Exon 14 of 22	ENST00000262623.4	NP_000695.2	P20648A0A384MR29Q658V6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ATP4A	ENST00000262623.4 link	c.2060C>T	p.Ser687Leu	missense_variant	Exon 14 of 22	1	NM_000704.3	ENSP00000262623.2	P20648
ATP4A	ENST00000592131.5 link	n.344C>T		non_coding_transcript_exon_variant	Exon 3 of 10	2
ATP4A	ENST00000592767.2 link	n.*171C>T		non_coding_transcript_exon_variant	Exon 3 of 5	3		ENSP00000472323.2	M0R249
ATP4A	ENST00000592767.2 link	n.*171C>T		3_prime_UTR_variant	Exon 3 of 5	3		ENSP00000472323.2	M0R249

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000411

AC:

AN:

243200

AF XY:

0.00

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:

0.0000474

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000117

AC:

AN:

1448838

Hom.:

Cov.:

AF XY:

0.0000153

AC XY:

AN XY:

718668

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33322

American (AMR)

AF:

0.00

AC:

AN:

44024

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25492

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39434

South Asian (SAS)

AF:

0.0000118

AC:

AN:

84692

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

53044

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

0.0000127

AC:

AN:

1103360

Other (OTH)

AF:

0.00

AC:

AN:

59760

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000346

Hom.:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 30, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2060C>T (p.S687L) alteration is located in exon 14 (coding exon 14) of the ATP4A gene. This alteration results from a C to T substitution at nucleotide position 2060, causing the serine (S) at amino acid position 687 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Uncertain

0.042

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.30

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.090

MetaRNN

Benign

0.25

MetaSVM

Uncertain

-0.10

MutationAssessor

Benign

0.65

PhyloP100

2.6

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.23

Sift

Uncertain

0.0010

Sift4G

Benign

0.089

Polyphen

0.019

Vest4

0.38

MutPred

0.42

Loss of disorder (P = 0.0435);

MVP

0.95

MPC

0.71

ClinPred

0.34

GERP RS

4.9

Varity_R

0.14

gMVP

0.60

Mutation Taster

=78/22

polymorphism

(source)

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

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19-35555537-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over