Genetic Variant NM_001374385.1:c.1286A>C (chr18-57688442-T-G) – 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.1286A>C(p.Glu429Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000432 in 1,614,202 control chromosomes in the GnomAD database, including 4 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 0.0019 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 3 hom. )

Consequence

ATP8B1
NM_001374385.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: 2.66

Publications

12 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=0.007627964).

BP6

Variant 18-57688442-T-G is Benign according to our data. Variant chr18-57688442-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 381740.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00194 (296/152308) while in subpopulation AFR AF = 0.00657 (273/41584). AF 95% confidence interval is 0.00592. There are 1 homozygotes in GnomAd4. There are 144 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 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
ATP8B1	NM_001374385.1	MANE Select	c.1286A>C	p.Glu429Ala	missense	Exon 13 of 28	NP_001361314.1
ATP8B1	NM_005603.6		c.1286A>C	p.Glu429Ala	missense	Exon 13 of 28	NP_005594.2
ATP8B1	NM_001374386.1		c.1136A>C	p.Glu379Ala	missense	Exon 12 of 27	NP_001361315.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ATP8B1	ENST00000648908.2	MANE Select	c.1286A>C	p.Glu429Ala	missense	Exon 13 of 28	ENSP00000497896.1
ATP8B1	ENST00000857621.1		c.1286A>C	p.Glu429Ala	missense	Exon 13 of 28	ENSP00000527680.1
ATP8B1	ENST00000857625.1		c.1286A>C	p.Glu429Ala	missense	Exon 14 of 29	ENSP00000527684.1

Frequencies

GnomAD3 genomes

AF:

0.00193

AC:

294

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00654

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000620

AC:

156

AN:

251446

AF XY:

0.000456

show subpopulations

Gnomad AFR exome

AF:

0.00597

Gnomad AMR exome

AF:

0.00119

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000703

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.000275

AC:

402

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000245

AC XY:

178

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00678

AC:

227

AN:

33480

American (AMR)

AF:

0.00116

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00503

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000387

AC:

AN:

1112012

Other (OTH)

AF:

0.000828

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

104

130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00194

AC:

296

AN:

152308

Hom.:

Cov.:

AF XY:

0.00193

AC XY:

144

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00657

AC:

273

AN:

41584

American (AMR)

AF:

0.00118

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68026

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000446

Hom.:

Bravo

AF:

0.00232

ESP6500AA

AF:

0.00545

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000675

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (2)

ATP8B1-related disorder (1)

Progressive familial intrahepatic cholestasis type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

Eigen

Benign

-0.12

Eigen_PC

Benign

0.092

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.75

M_CAP

Benign

0.016

MetaRNN

Benign

0.0076

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.2

PhyloP100

2.7

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.2

REVEL

Benign

0.13

Sift

Benign

0.24

Sift4G

Benign

0.37

Polyphen

0.0010

Vest4

0.40

MVP

0.78

ClinPred

0.018

GERP RS

5.7

Varity_R

0.047

gMVP

0.86

Mutation Taster

=94/6

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

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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