Genetic Variant NM_001374385.1:c.208G>A (chr18-57706561-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001374385.1(ATP8B1):c.208G>A(p.Asp70Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00353 in 1,613,854 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0036 ( 16 hom. )

Consequence

ATP8B1
NM_001374385.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:8B:6

Conservation

PhyloP100: 5.18

Publications

28 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009497732).

BP6

Variant 18-57706561-C-T is Benign according to our data. Variant chr18-57706561-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 7271.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00358 (5237/1461664) while in subpopulation MID AF = 0.0222 (128/5766). AF 95% confidence interval is 0.0191. There are 16 homozygotes in GnomAdExome4. There are 2643 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 16 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.208G>A	p.Asp70Asn	missense	Exon 3 of 28	NP_001361314.1	O43520
ATP8B1	NM_005603.6		c.208G>A	p.Asp70Asn	missense	Exon 3 of 28	NP_005594.2	O43520
ATP8B1	NM_001374386.1		c.130-1893G>A		intron	N/A	NP_001361315.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP8B1	ENST00000648908.2	MANE Select	c.208G>A	p.Asp70Asn	missense	Exon 3 of 28	ENSP00000497896.1	O43520
ATP8B1	ENST00000857621.1		c.208G>A	p.Asp70Asn	missense	Exon 3 of 28	ENSP00000527680.1
ATP8B1	ENST00000857625.1		c.208G>A	p.Asp70Asn	missense	Exon 4 of 29	ENSP00000527684.1

Frequencies

GnomAD3 genomes

AF:

0.00303

AC:

461

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00386

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.00425

Gnomad OTH

AF:

0.00909

GnomAD2 exomes

AF:

0.00319

AC:

800

AN:

251108

AF XY:

0.00324

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00177

Gnomad ASJ exome

AF:

0.0100

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.000462

Gnomad NFE exome

AF:

0.00450

Gnomad OTH exome

AF:

0.00522

GnomAD4 exome

AF:

0.00358

AC:

5237

AN:

1461664

Hom.:

Cov.:

AF XY:

0.00363

AC XY:

2643

AN XY:

727108

show subpopulations

African (AFR)

AF:

0.00143

AC:

AN:

33480

American (AMR)

AF:

0.00197

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00953

AC:

249

AN:

26120

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39692

South Asian (SAS)

AF:

0.00218

AC:

188

AN:

86198

European-Finnish (FIN)

AF:

0.000393

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.0222

AC:

128

AN:

5766

European-Non Finnish (NFE)

AF:

0.00382

AC:

4247

AN:

1111898

Other (OTH)

AF:

0.00440

AC:

266

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

261

522

783

1044

1305

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

296

444

592

740

<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:

0.00302

AC:

459

AN:

152190

Hom.:

Cov.:

AF XY:

0.00312

AC XY:

232

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.00128

AC:

AN:

41510

American (AMR)

AF:

0.00386

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00166

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0000944

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00426

AC:

290

AN:

68008

Other (OTH)

AF:

0.00900

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

106

132

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:

0.00391

Hom.:

Bravo

AF:

0.00292

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00302

AC:

ExAC

AF:

0.00314

AC:

381

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00551

EpiControl

AF:

0.00510

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Cholestasis, intrahepatic, of pregnancy, 1 (3)

Progressive familial intrahepatic cholestasis type 1 (3)

Benign recurrent intrahepatic cholestasis type 1 (2)

ATP8B1-related disorder (1)

not specified (1)

Progressive familial intrahepatic cholestasis type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

Eigen

Benign

0.16

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.077

MetaRNN

Benign

0.0095

MetaSVM

Benign

-0.75

MutationAssessor

Benign

0.94

PhyloP100

5.2

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.23

Sift

Benign

0.26

Sift4G

Benign

0.28

Polyphen

1.0

Vest4

0.39

MVP

0.79

ClinPred

0.036

GERP RS

5.1

Varity_R

0.094

gMVP

0.60

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over