rs144656719

Positions:

chr18-57661335-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBS1_SupportingBS2

The NM_001374385.1(ATP8B1):c.2546G>A(p.Arg849Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000898 in 1,613,952 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000095 ( 3 hom. )

Consequence

ATP8B1
NM_001374385.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: -1.28

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:

(HGNC:):

links:

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

ATP8B1-AS1 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 gene, where missense usually causes diseases (based on misZ statistic), ATP8B1. . Trascript score misZ 3.3227 (greater than threshold 3.09). GenCC has associacion of gene with progressive familial intrahepatic cholestasis type 1, cholestasis, intrahepatic, of pregnancy, 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.014357299).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000951 (139/1461894) while in subpopulation MID AF= 0.00832 (48/5768). AF 95% confidence interval is 0.00645. There are 3 homozygotes in gnomad4_exome. There are 70 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP8B1	NM_001374385.1 linkuse as main transcript	c.2546G>A	p.Arg849Gln	missense_variant	22/28	ENST00000648908.2	NP_001361314.1
ATP8B1-AS1	NR_164148.1 linkuse as main transcript	n.683-6671C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
ATP8B1	ENST00000648908.2 linkuse as main transcript	c.2546G>A	p.Arg849Gln	missense_variant	22/28		NM_001374385.1	ENSP00000497896	P1
	ENST00000588925.5 linkuse as main transcript	n.570+19283C>T		intron_variant, non_coding_transcript_variant		2
ATP8B1-AS1	ENST00000592201.1 linkuse as main transcript	n.664-6671C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

151940

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000481

GnomAD3 exomes

AF:

0.0000915

AC:

AN:

251432

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000704

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.0000951

AC:

139

AN:

1461894

Hom.:

Cov.:

AF XY:

0.0000963

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000359

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000342

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.0000395

AC:

AN:

152058

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000476

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.0000680

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 24, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 2016	The R849Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R849Q variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R849Q variant has been observed as homozygous in a single unaffected individual sent for whole exome sequence analysis at GeneDx. The R849Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 19, 2022	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 849 of the ATP8B1 protein (p.Arg849Gln). This variant is present in population databases (rs144656719, gnomAD 0.02%). This missense change has been observed in individual(s) with intrahepatic cholestasis (PMID: 26126923). ClinVar contains an entry for this variant (Variation ID: 383293). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Benign recurrent intrahepatic cholestasis type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 06, 2019

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Progressive familial intrahepatic cholestasis type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 28, 2017

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. -

Cholestasis, intrahepatic, of pregnancy, 1;C4551898:Progressive familial intrahepatic cholestasis type 1;C4551899:Benign recurrent intrahepatic cholestasis type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.41

CADD

Benign

4.0

DANN

Benign

0.90

DEOGEN2

Benign

0.076

T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.071

LIST_S2

Benign

0.71

.;T

M_CAP

Benign

0.026

MetaRNN

Benign

0.014

T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.61

N;N

MutationTaster

Benign

0.79

N;N

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.48

N;.

REVEL

Benign

0.15

Sift

Benign

0.50

T;.

Sift4G

Benign

0.34

T;.

Polyphen

0.0010

B;B

Vest4

0.15

MVP

0.47

ClinPred

0.026

GERP RS

-3.0

Varity_R

0.028

gMVP

0.42

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