Genetic Variant ATP8B4:p.Asn225Ser (chr15-49987465-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_024837.4(ATP8B4):c.674A>G(p.Asn225Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 1,613,206 control chromosomes in the GnomAD database, including 47,009 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.28 ( 6255 hom., cov: 32)

Exomes 𝑓: 0.23 ( 40754 hom. )

Consequence

ATP8B4
NM_024837.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.184

Publications

28 publications found

Variant links:

Genes affected

ATP8B4 (HGNC:13536): (ATPase phospholipid transporting 8B4 (putative)) This gene encodes a member of the cation transport ATPase (P-type) family and type IV subfamily. The encoded protein is involved in phospholipid transport in the cell membrane. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2013]

ATP8B4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0010026991).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.373 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP8B4	NM_024837.4 link	c.674A>G	p.Asn225Ser	missense_variant	Exon 10 of 28	ENST00000284509.11	NP_079113.2	Q8TF62Q6PG43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP8B4	ENST00000284509.11 link	c.674A>G	p.Asn225Ser	missense_variant	Exon 10 of 28	5	NM_024837.4	ENSP00000284509.6		Q8TF62

Frequencies

GnomAD3 genomes

AF:

0.276

AC:

41980

AN:

151922

Hom.:

6257

Cov.:

show subpopulations

Gnomad AFR

AF:

0.379

Gnomad AMI

AF:

0.363

Gnomad AMR

AF:

0.214

Gnomad ASJ

AF:

0.0964

Gnomad EAS

AF:

0.341

Gnomad SAS

AF:

0.210

Gnomad FIN

AF:

0.330

Gnomad MID

AF:

0.146

Gnomad NFE

AF:

0.230

Gnomad OTH

AF:

0.215

GnomAD2 exomes

AF:

0.247

AC:

61824

AN:

250714

AF XY:

0.241

show subpopulations

Gnomad AFR exome

AF:

0.383

Gnomad AMR exome

AF:

0.222

Gnomad ASJ exome

AF:

0.0975

Gnomad EAS exome

AF:

0.352

Gnomad FIN exome

AF:

0.323

Gnomad NFE exome

AF:

0.228

Gnomad OTH exome

AF:

0.211

GnomAD4 exome

AF:

0.231

AC:

337618

AN:

1461166

Hom.:

40754

Cov.:

AF XY:

0.230

AC XY:

167288

AN XY:

726872

show subpopulations

African (AFR)

AF:

0.383

AC:

12811

AN:

33440

American (AMR)

AF:

0.221

AC:

9858

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.0968

AC:

2528

AN:

26120

East Asian (EAS)

AF:

0.361

AC:

14308

AN:

39662

South Asian (SAS)

AF:

0.207

AC:

17864

AN:

86194

European-Finnish (FIN)

AF:

0.313

AC:

16711

AN:

53388

Middle Eastern (MID)

AF:

0.123

AC:

710

AN:

5764

European-Non Finnish (NFE)

AF:

0.224

AC:

249402

AN:

1111576

Other (OTH)

AF:

0.222

AC:

13426

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

14342

28684

43025

57367

71709

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8628

17256

25884

34512

43140

<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:

0.276

AC:

42004

AN:

152040

Hom.:

6255

Cov.:

AF XY:

0.278

AC XY:

20681

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.378

AC:

15689

AN:

41464

American (AMR)

AF:

0.214

AC:

3267

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.0964

AC:

334

AN:

3466

East Asian (EAS)

AF:

0.341

AC:

1764

AN:

5166

South Asian (SAS)

AF:

0.210

AC:

1014

AN:

4830

European-Finnish (FIN)

AF:

0.330

AC:

3483

AN:

10568

Middle Eastern (MID)

AF:

0.143

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.230

AC:

15629

AN:

67976

Other (OTH)

AF:

0.215

AC:

452

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1545

3090

4635

6180

7725

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

426

852

1278

1704

2130

<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:

0.235

Hom.:

18148

Bravo

AF:

0.271

TwinsUK

AF:

0.225

AC:

836

ALSPAC

AF:

0.206

AC:

794

ESP6500AA

AF:

0.378

AC:

1661

ESP6500EA

AF:

0.217

AC:

1866

ExAC

AF:

0.251

AC:

30416

Asia WGS

AF:

0.271

AC:

940

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.63

CADD

Benign

2.1

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.086

T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.76

LIST_S2

Uncertain

0.89

D;.

MetaRNN

Benign

0.0010

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.45

N;N

PhyloP100

-0.18

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.60

N;N

REVEL

Benign

0.13

Sift

Benign

0.32

T;T

Sift4G

Benign

0.24

T;T

Polyphen

0.0

B;B

Vest4

0.057

MPC

0.045

ClinPred

0.0017

GERP RS

-2.2

Varity_R

0.049

gMVP

0.29

Mutation Taster

=99/1

polymorphism (auto)

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over