rs150860808

Positions:

• chr18-57695198-A-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:4
• Conservation: PhyloP100: 0.0120

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ATP8B1
• 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: {Uncertain_significance=5, Likely_benign=1, Benign=1}. 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/exons	MANE	UniProt
ATP8B1	NM_001374385.1	c.913T>A	p.Phe305Ile	missense_variant	10/28	ENST00000648908.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP8B1	ENST00000648908.2	c.913T>A	p.Phe305Ile	missense_variant	10/28		NM_001374385.1	P1
	ENST00000588925.5	n.571-36216A>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 180 AN: 152228 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.00118 AC XY: 161 AN XY: 135914

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.: 8 Cov.: 32 AF XY: 0.00172 AC XY: 1254 AN XY: 727222

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.: 0 Cov.: 32 AF XY: 0.00109 AC XY: 81 AN XY: 74500

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.: 1

Bravo AF: 0.00147

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00101 AC: 122

EpiCase AF: 0.00224

EpiControl AF: 0.00237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2024	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	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. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 15, 2016	- -

ATP8B1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 02, 2024

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. Recently, 8 homozygotes, mostly in individuals of European descent, have been identified in the gnomAD V4 dataset. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Progressive familial intrahepatic cholestasis type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.42	T
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	N
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
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	T
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

Other links and lift over

dbSNP: rs150860808; hg19: chr18-55362430;