Genetic Variant NM_024490.4:c.3894G>C (chr15-25679947-C-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1298K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.47 ( 17265 hom., cov: 33)

Exomes 𝑓: 0.47 ( 160695 hom. )

Consequence

ATP10A
NM_024490.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -1.29

Publications

33 publications found

Variant links:

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]

ATP10A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 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 VariationId is 3059660.Status of the report is no_assertion_criteria_provided, 0 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 rank	MANE	Protein	UniProt
ATP10A	NM_024490.4 link	c.3894G>C	p.Arg1298Ser	missense_variant	Exon 21 of 21	ENST00000555815.7	NP_077816.1	O60312-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP10A	ENST00000555815.7 link	c.3894G>C	p.Arg1298Ser	missense_variant	Exon 21 of 21	5	NM_024490.4	ENSP00000450480.2		O60312-1

Frequencies

GnomAD3 genomes

AF:

0.473

AC:

71863

AN:

151914

Hom.:

17242

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.450

AC:

111310

AN:

247528

AF XY:

0.454

show subpopulations

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 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.:

AF XY:

0.468

AC XY:

336467

AN XY:

718898

show subpopulations

African (AFR)

AF:

0.517

AC:

17224

AN:

33292

American (AMR)

AF:

0.358

AC:

15970

AN:

44564

Ashkenazi Jewish (ASJ)

AF:

0.379

AC:

9881

AN:

26042

East Asian (EAS)

AF:

0.338

AC:

13325

AN:

39380

South Asian (SAS)

AF:

0.462

AC:

39778

AN:

86082

European-Finnish (FIN)

AF:

0.511

AC:

26493

AN:

51806

Middle Eastern (MID)

AF:

0.424

AC:

2432

AN:

5730

European-Non Finnish (NFE)

AF:

0.477

AC:

526528

AN:

1103260

Other (OTH)

AF:

0.462

AC:

27633

AN:

59774

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

20503

41007

61510

82014

102517

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15656

31312

46968

62624

78280

<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

AF:

0.473

AC:

71940

AN:

152032

Hom.:

17265

Cov.:

AF XY:

0.469

AC XY:

34875

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.518

AC:

21495

AN:

41464

American (AMR)

AF:

0.378

AC:

5780

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.387

AC:

1342

AN:

3472

East Asian (EAS)

AF:

0.359

AC:

1850

AN:

5158

South Asian (SAS)

AF:

0.461

AC:

2221

AN:

4816

European-Finnish (FIN)

AF:

0.518

AC:

5472

AN:

10564

Middle Eastern (MID)

AF:

0.428

AC:

125

AN:

292

European-Non Finnish (NFE)

AF:

0.473

AC:

32145

AN:

67968

Other (OTH)

AF:

0.459

AC:

967

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

2024

4049

6073

8098

10122

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

650

1300

1950

2600

3250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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: no assertion criteria provided

LINK: link

Submissions by phenotype

ATP10A-related disorder

Benign:1

Oct 16, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

BayesDel_noAF

Benign

-0.69

CADD

Benign

5.9

(source)

DANN

Benign

0.49

DEOGEN2

Benign

0.0056

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.22

MetaRNN

Benign

0.000032

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-1.0

PhyloP100

-1.3

PrimateAI

Benign

0.33

PROVEAN

Benign

2.5

REVEL

Benign

0.038

Sift

Benign

0.88

Sift4G

Benign

0.66

Polyphen

0.0

Vest4

0.017

MutPred

0.26

Loss of MoRF binding (P = 0.0118);

MPC

0.18

ClinPred

0.0013

GERP RS

0.74

Varity_R

0.080

gMVP

0.34

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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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