19-35558582-G-A

Variant names:

• chr19-35558582-G-A
• rs756885561
• NM_000704.3:c.1360C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000704.3(ATP4A):​c.1360C>T​(p.Pro454Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,450,818 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: ATP4A NM_000704.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.75

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]

ENSG00000283907 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17473543).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP4A	NM_000704.3	c.1360C>T	p.Pro454Ser	missense_variant	Exon 9 of 22	ENST00000262623.4	NP_000695.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP4A	ENST00000262623.4	c.1360C>T	p.Pro454Ser	missense_variant	Exon 9 of 22	1	NM_000704.3	ENSP00000262623.2
ENSG00000283907	ENST00000638356.1	n.72+555G>A		intron_variant	Intron 1 of 2	1
ENSG00000283907	ENST00000702449.1	n.100+555G>A		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1450818 Hom.: 0 Cov.: 33 AF XY: 0.00000416 AC XY: 3 AN XY: 720542

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000361

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1360C>T (p.P454S) alteration is located in exon 9 (coding exon 9) of the ATP4A gene. This alteration results from a C to T substitution at nucleotide position 1360, causing the proline (P) at amino acid position 454 to be replaced by a serine (S). 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	0.16
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.096	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	0.0031	D
MutationAssessor	Benign	0.14	N
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	0.22	N
REVEL	Uncertain	0.29
Sift	Benign	0.20	T
Sift4G	Benign	0.86	T
Polyphen		0.046	B
Vest4		0.17
MutPred		0.31		Gain of ubiquitination at K455 (P = 0.0846);
MVP		0.94
MPC		0.89
ClinPred		0.28	T
GERP RS		4.1
Varity_R		0.093
gMVP		0.59

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: rs756885561; hg19: chr19-36049484;