rs34018205

chr18-57688442-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 2.66

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 -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ATP8B1
• 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: {Benign=3, Likely_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 GnomAdExome at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP8B1	NM_001374385.1	c.1286A>C	p.Glu429Ala	missense_variant	13/28	ENST00000648908.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP8B1	ENST00000648908.2	c.1286A>C	p.Glu429Ala	missense_variant	13/28		NM_001374385.1	P1
	ENST00000588925.5	n.571-42972T>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 294 AN: 152190 Hom.: 1 Cov.: 32

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.: 2 AF XY: 0.000456 AC XY: 62 AN XY: 135898

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.: 3 Cov.: 31 AF XY: 0.000245 AC XY: 178 AN XY: 727248

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.: 1 Cov.: 32 AF XY: 0.00193 AC XY: 144 AN XY: 74468

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.: 1

Bravo AF: 0.00232

ESP6500AA AF: 0.00545 AC: 24

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000675 AC: 82

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	ATP8B1: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 16, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 2018	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. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 21, 2022	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. -

ATP8B1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 22, 2022

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 03, 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. 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	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.13	T;T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.092
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0076	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.59	T
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	T
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

Other links and lift over

dbSNP: rs34018205; hg19: chr18-55355674;