rs121909101

chr18-57674993-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP2 PP3_Strong PP5_Very_Strong

The NM_001374385.1(ATP8B1):c.1660G>A(p.Asp554Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: ATP8B1 NM_001374385.1 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 7.81

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 Pathogenic. Variant got 13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ATP8B1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95
• PP5: Variant 18-57674993-C-T is Pathogenic according to our data. Variant chr18-57674993-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP8B1	NM_001374385.1	c.1660G>A	p.Asp554Asn	missense_variant	16/28	ENST00000648908.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP8B1	ENST00000648908.2	c.1660G>A	p.Asp554Asn	missense_variant	16/28		NM_001374385.1	P1
	ENST00000588925.5	n.570+32941C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461830 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727212

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 02, 2023	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 554 of the ATP8B1 protein (p.Asp554Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cholestasis (PMID: 11093741). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7269). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATP8B1 protein function. Experimental studies have shown that this missense change affects ATP8B1 function (PMID: 19731236, 19918981). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 22, 2022	Published functional studies demonstrate a damaging effect with decreased protein expression and abnormal subcellular localization (Folmer et al., 2009; van der Velden et al., 2010); In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect; This variant is associated with the following publications: (PMID: 28222887, 29973134, 19918981, 20852622, 15736649, 15736650, 28195083, 28937026, 33666275, 34016879, 19731236, 11093741, 24627769) -

Progressive familial intrahepatic cholestasis type 1 Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2010	- -
not provided, no classification provided	literature only	GeneReviews	-	Variant common in persons of Inuit ancestry from eastern Nunavut (Canadian Arctic), in both western and eastern Greenland, and in 1 kindred with Athabascan and Norwegian ancestry -

ATP8B1-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 16, 2024

The ATP8B1 c.1660G>A variant is predicted to result in the amino acid substitution p.Asp554Asn. This variant has been reported in the homozygous state in individuals with progressive familial intrahepatic cholestasis (Sharma et al. 2018. PubMed ID: 29973134; van Wessel et al. 2021. PubMed ID: 33666275; Table S2, Hertel et al. 2021. PubMed ID: 34016879). Functional studies have found that the p.Asp554Asn substitution significantly reduces protein expression and causes mislocalization (Folmer et al. 2009. PubMed ID: 19731236; van der Velden et al. 2010. PubMed ID: 19918981). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D;D
Eigen	Pathogenic	0.84
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.7	H;H
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-4.8	D;.
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.79		Loss of catalytic residue at G556 (P = 0.1525);Loss of catalytic residue at G556 (P = 0.1525);
MVP		0.89
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.92
gMVP		0.94

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: rs121909101; hg19: chr18-55342225;