dbSNP rs150860808: ATP8B1:p.Phe305Ile (chr18-57695198-A-T) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2

The NM_001374385.1(ATP8B1):c.913T>A(p.Phe305Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,614,202 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 8 hom. )

Consequence

ATP8B1
NM_001374385.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:4

Conservation

PhyloP100: 0.0120

Publications

7 publications found

Variant links:

Genes affected

ATP8B1 (HGNC:3706): (ATPase phospholipid transporting 8B1) This gene encodes a member of the P-type cation transport ATPase family, which belongs to the subfamily of aminophospholipid-transporting ATPases. The aminophospholipid translocases transport phosphatidylserine and phosphatidylethanolamine from one side of a bilayer to another. Mutations in this gene may result in progressive familial intrahepatic cholestasis type 1 and in benign recurrent intrahepatic cholestasis. [provided by RefSeq, Jul 2008]

ATP8B1 links:

ATP8B1-AS1 (HGNC:56042): (ATP8B1 antisense RNA 1)

ATP8B1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001374385.1

BP4

Computational evidence support a benign effect (MetaRNN=0.013626218).

BP6

Variant 18-57695198-A-T is Benign according to our data. Variant chr18-57695198-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 289557.

BS2

High Homozygotes in GnomAdExome4 at 8 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374385.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP8B1	NM_001374385.1	MANE Select	c.913T>A	p.Phe305Ile	missense	Exon 10 of 28	NP_001361314.1	O43520
ATP8B1	NM_005603.6		c.913T>A	p.Phe305Ile	missense	Exon 10 of 28	NP_005594.2	O43520
ATP8B1	NM_001374386.1		c.763T>A	p.Phe255Ile	missense	Exon 9 of 27	NP_001361315.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP8B1	ENST00000648908.2	MANE Select	c.913T>A	p.Phe305Ile	missense	Exon 10 of 28	ENSP00000497896.1	O43520
ATP8B1	ENST00000857621.1		c.913T>A	p.Phe305Ile	missense	Exon 10 of 28	ENSP00000527680.1
ATP8B1	ENST00000857625.1		c.913T>A	p.Phe305Ile	missense	Exon 11 of 29	ENSP00000527684.1

Frequencies

GnomAD3 genomes

AF:

0.00118

AC:

180

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00207

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00118

AC:

296

AN:

251422

AF XY:

0.00118

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000838

Gnomad ASJ exome

AF:

0.00427

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00187

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.00184

AC:

2691

AN:

1461856

Hom.:

Cov.:

AF XY:

0.00172

AC XY:

1254

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.000917

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00371

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00214

AC:

2383

AN:

1112002

Other (OTH)

AF:

0.00243

AC:

147

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

145

290

434

579

724

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

192

288

384

480

<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:

0.00118

AC:

180

AN:

152346

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.000216

AC:

AN:

41590

American (AMR)

AF:

0.00105

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00207

AC:

141

AN:

68032

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00204

Hom.:

Bravo

AF:

0.00147

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.00101

AC:

122

EpiCase

AF:

0.00224

EpiControl

AF:

0.00237

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

not specified (2)

Progressive familial intrahepatic cholestasis type 1 (2)

ATP8B1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.39

CADD

Benign

5.8

(source)

DANN

Benign

0.86

DEOGEN2

Uncertain

0.73

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.66

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.014

MetaSVM

Benign

-0.60

MutationAssessor

Benign

1.5

PhyloP100

0.012

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.29

Sift

Benign

0.095

Sift4G

Benign

0.13

Polyphen

0.0

Vest4

0.23

MVP

0.36

ClinPred

0.0077

GERP RS

-7.6

Varity_R

0.089

gMVP

0.77

Mutation Taster

=89/11

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over