NM_001374385.1:c.1286A>C

Variant names:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_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. 14/21 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

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:

ENSG00000267787 (HGNC:):

ENSG00000267787 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP2

Missense variant in the ATP8B1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 21 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Trascript score misZ: 3.3227 (above the threshold of 3.09). GenCC associations: The gene is linked to progressive familial intrahepatic cholestasis type 1, cholestasis, intrahepatic, of pregnancy, 1.

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 id is 381740.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=3, Uncertain_significance=2}.

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP8B1	NM_001374385.1 link	c.1286A>C	p.Glu429Ala	missense_variant	Exon 13 of 28	ENST00000648908.2	NP_001361314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP8B1	ENST00000648908.2 link	c.1286A>C	p.Glu429Ala	missense_variant	Exon 13 of 28		NM_001374385.1	ENSP00000497896.1		O43520

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

GnomAD3 exomes

AF:

0.000620

AC:

156

AN:

251446

Hom.:

AF XY:

0.000456

AC XY:

AN XY:

135898

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 SAS 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

Gnomad4 AFR exome

AF:

0.00678

Gnomad4 AMR exome

AF:

0.00116

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000387

Gnomad4 OTH exome

AF:

0.000828

GnomAD4 genome

AF:

0.00194

AC:

296

AN:

152308

Hom.:

Cov.:

AF XY:

0.00193

AC XY:

144

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00657

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000361

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Jul 16, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 24, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant of uncertain significance has been identified in the ATP8B1 gene. The E429A variant has previously been identified as heterozygous in three individuals with benign recurrent intrahepatic cholestasis-1 or progressive familial intrahepatic cholestasis-1, however a second variant in ATP8B1 was not identified in any of these individuals (Klomp et al., 2004). It has also been reported as heterozygous in a single patient with chronic pancreatitis (van der Woerd et al., 2013). However, the 1000 Genomes Project Consortium reports E429A was observed in 13/1322 (0.98%) alleles from individuals of African background, including 9/198 (4.6%) of alleles from individuals from the Luhya population in Kenya. The E429A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

May 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATP8B1: BS2 -

not specified

Benign:2

Feb 21, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATP8B1 c.1286A>C (p.Glu429Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00062 in 251446 control chromosomes, predominantly at a frequency of 0.006 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATP8B1 causing Familial Intrahepatic Cholestasis phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Although reported in the literarue, to our knowledge, no occurrence of c.1286A>C in individuals affected with Familial Intrahepatic Cholestasis and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Benign, n=2; VUS, n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

Dec 14, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ATP8B1-related disorder

Benign:1

Dec 22, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Progressive familial intrahepatic cholestasis type 1

Benign:1

Oct 03, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

T;T

Eigen

Benign

-0.12

Eigen_PC

Benign

0.092

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.75

.;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.0076

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.2

L;L

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.2

N;.

REVEL

Benign

0.13

Sift

Benign

0.24

T;.

Sift4G

Benign

0.37

T;.

Polyphen

0.0010

B;B

Vest4

0.40

MVP

0.78

ClinPred

0.018

GERP RS

5.7

Varity_R

0.047

gMVP

0.86

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over