15-25679947-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_024490.4(ATP10A):c.3894G>C(p.Arg1298Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.469 in 1,601,962 control chromosomes in the GnomAD database, including 177,960 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 Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.47 (17265 hom., cov: 33)
  • Exomes 𝑓: 0.47 (160695 hom.)
• Consequence: ATP10A NM_024490.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.29

Genes affected

ATP10A (HGNC:13542): (ATPase phospholipid transporting 10A (putative)) The protein encoded by this gene belongs to the family of P-type cation transport ATPases, and to the subfamily of aminophospholipid-transporting ATPases. The aminophospholipid translocases transport phosphatidylserine and phosphatidylethanolamine from one side of a bilayer to another. This gene is maternally expressed. It maps within the most common interval of deletion responsible for Angelman syndrome, also known as 'happy puppet syndrome'. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.2212014E-5).
• BP6: Variant 15-25679947-C-G is Benign according to our data. Variant chr15-25679947-C-G is described in ClinVar as [Benign]. Clinvar id is 3059660.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.513 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP10A	NM_024490.4	c.3894G>C	p.Arg1298Ser	missense_variant	21/21	ENST00000555815.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP10A	ENST00000555815.7	c.3894G>C	p.Arg1298Ser	missense_variant	21/21	5	NM_024490.4	P1

Frequencies

GnomAD3 genomes AF: 0.473 AC: 71863 AN: 151914 Hom.: 17242 Cov.: 33

Gnomad AFR AF: 0.518

Gnomad AMI AF: 0.599

Gnomad AMR AF: 0.379

Gnomad ASJ AF: 0.387

Gnomad EAS AF: 0.359

Gnomad SAS AF: 0.461

Gnomad FIN AF: 0.518

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.473

Gnomad OTH AF: 0.459

GnomAD3 exomes AF: 0.450 AC: 111310 AN: 247528 Hom.: 25615 AF XY: 0.454 AC XY: 61122 AN XY: 134490

Gnomad AFR exome AF: 0.516

Gnomad AMR exome AF: 0.350

Gnomad ASJ exome AF: 0.377

Gnomad EAS exome AF: 0.364

Gnomad SAS exome AF: 0.464

Gnomad FIN exome AF: 0.520

Gnomad NFE exome AF: 0.476

Gnomad OTH exome AF: 0.433

GnomAD4 exome AF: 0.468 AC: 679264 AN: 1449930 Hom.: 160695 Cov.: 61 AF XY: 0.468 AC XY: 336467 AN XY: 718898

Gnomad4 AFR exome AF: 0.517

Gnomad4 AMR exome AF: 0.358

Gnomad4 ASJ exome AF: 0.379

Gnomad4 EAS exome AF: 0.338

Gnomad4 SAS exome AF: 0.462

Gnomad4 FIN exome AF: 0.511

Gnomad4 NFE exome AF: 0.477

Gnomad4 OTH exome AF: 0.462

GnomAD4 genome AF: 0.473 AC: 71940 AN: 152032 Hom.: 17265 Cov.: 33 AF XY: 0.469 AC XY: 34875 AN XY: 74312

Gnomad4 AFR AF: 0.518

Gnomad4 AMR AF: 0.378

Gnomad4 ASJ AF: 0.387

Gnomad4 EAS AF: 0.359

Gnomad4 SAS AF: 0.461

Gnomad4 FIN AF: 0.518

Gnomad4 NFE AF: 0.473

Gnomad4 OTH AF: 0.459

Alfa AF: 0.462 Hom.: 5131

Bravo AF: 0.463

TwinsUK AF: 0.480 AC: 1778

ALSPAC AF: 0.479 AC: 1845

ESP6500AA AF: 0.520 AC: 2289

ESP6500EA AF: 0.476 AC: 4090

ExAC AF: 0.459 AC: 55651

EpiCase AF: 0.475

EpiControl AF: 0.478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ATP10A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 16, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	5.9
Dann	Benign	0.49
DEOGEN2	Benign	0.0056	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.000032	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.0	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	2.5	N
REVEL	Benign	0.038
Sift	Benign	0.88	T
Sift4G	Benign	0.66	T
Polyphen		0.0	B
Vest4		0.017
MutPred		0.26		Loss of MoRF binding (P = 0.0118);
MPC		0.18
ClinPred		0.0013	T
GERP RS		0.74
Varity_R		0.080
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs3816800; hg19: chr15-25925094; COSMIC: COSV63515611; COSMIC: COSV63515611;