rs150860808

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_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. 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 0.0012 ( 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

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 -8 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=0.013626218).

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 id is 289557.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=5}. Variant chr18-57695198-A-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP8B1	NM_001374385.1 link	c.913T>A	p.Phe305Ile	missense_variant	Exon 10 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.913T>A	p.Phe305Ile	missense_variant	Exon 10 of 28		NM_001374385.1	ENSP00000497896.1		O43520

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

GnomAD3 exomes

AF:

0.00118

AC:

296

AN:

251422

Hom.:

AF XY:

0.00118

AC XY:

161

AN XY:

135914

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 SAS exome

AF:

0.0000653

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

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000917

Gnomad4 ASJ exome

AF:

0.00371

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.00214

Gnomad4 OTH exome

AF:

0.00243

GnomAD4 genome

AF:

0.00118

AC:

180

AN:

152346

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.000216

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00207

Gnomad4 OTH

AF:

0.00142

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:3

Jul 02, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1 -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 21, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in the heterozygous state in individuals with intrahepatic cholestasis of pregnancy, chronic pancreatitis, or cryptogenic cholestasis in whom a second variant in ATP8B1 was not identified. This variant was also identified in multiple healthy control individuals (PMID: 15888793, 24260417, 29238877); This variant is associated with the following publications: (PMID: Barkaoui[Article]2018, 33666275, 24260417, 29238877, 28733223, 34679599, 15888793) -

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Progressive familial intrahepatic cholestasis type 1

Uncertain:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Feb 16, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

not specified

Uncertain:1Benign:1

Jul 15, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 18, 2022

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATP8B1 c.913T>A (p.Phe305Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 251422 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATP8B1 causing Familial Intrahepatic Cholestasis (0.0012 vs 0.0022), allowing no conclusion about variant significance. c.913T>A has been reported in the literature in individuals affected with intrahepatic cholestasis of pregnancy (Mullenbach_2005) or FIC1 deficiency (van Wessel_2021). These reports do not provide unequivocal conclusions about association of the variant with Familial Intrahepatic Cholestasis. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign n=1, VUS n=3). Based on the evidence outlined above, the variant was classified as uncertain significance. -

ATP8B1-related disorder

Uncertain:1

May 08, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATP8B1 c.913T>A variant is predicted to result in the amino acid substitution p.Phe305Ile. This variant has been reported in patients with ATP8B1-related disease, including PFIC, cryptogenic cholestasis, intrahepatic cholestasis of pregnancy, and chronic pancreatitis (Müllenbach et al. 2005. PubMed ID: 15888793; van der Woerd et al. 2013. PubMed ID: 24260417; Dröge et al. 2017. PubMed ID: 28733223; Vitale et al. 2018. PubMed ID: 29238877). However, this variant has also been documented in healthy controls (Müllenbach et al. 2005. PubMed ID: 15888793; Woerd et al. 2013. PubMed ID: 24260417). This variant is found at an allele frequency of up to 0.42% in individuals of Ashkenazi Jewish descent in gnomAD. Additionally, in gnomAD v4 (available only on GRCh38), this variant is reported in 0.36% of individuals of Ashkenazi Jewish descent, including 8 homozygotes that were identified mostly in individuals of European descent. This population data is not consistent with this variant being a primary cause of disease. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.39

CADD

Benign

5.8

DANN

Benign

0.86

DEOGEN2

Uncertain

0.73

D;D

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.66

.;T

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.014

T;T

MetaSVM

Benign

-0.60

MutationAssessor

Benign

1.5

L;L

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-2.5

D;.

REVEL

Benign

0.29

Sift

Benign

0.095

T;.

Sift4G

Benign

0.13

T;.

Polyphen

0.0

B;B

Vest4

0.23

MVP

0.36

ClinPred

0.0077

GERP RS

-7.6

Varity_R

0.089

gMVP

0.77

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