rs3745079

Positions:

• chr18-57706535-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001374385.1(ATP8B1):​c.234C>G​(p.His78Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,614,062 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (66 hom.)
• Consequence: ATP8B1 NM_001374385.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.14

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 -19 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=0.0015209615).
• BP6: Variant 18-57706535-G-C is Benign according to our data. Variant chr18-57706535-G-C is described in ClinVar as [Benign]. Clinvar id is 259818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-57706535-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00202 (307/152284) while in subpopulation EAS AF= 0.0447 (232/5190). AF 95% confidence interval is 0.04. There are 11 homozygotes in gnomad4. There are 179 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP8B1	NM_001374385.1	c.234C>G	p.His78Gln	missense_variant	3/28	ENST00000648908.2	NP_001361314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP8B1	ENST00000648908.2	c.234C>G	p.His78Gln	missense_variant	3/28		NM_001374385.1	ENSP00000497896	P1
	ENST00000588925.5	n.571-24879G>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 308 AN: 152166 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0448

Gnomad SAS AF: 0.00809

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00437 AC: 1097 AN: 251254 Hom.: 25 AF XY: 0.00426 AC XY: 578 AN XY: 135814

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0471

Gnomad SAS exome AF: 0.00634

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00190 AC: 2772 AN: 1461778 Hom.: 66 Cov.: 31 AF XY: 0.00203 AC XY: 1479 AN XY: 727174

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000403

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0494

Gnomad4 SAS exome AF: 0.00609

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000989

Gnomad4 OTH exome AF: 0.00227

GnomAD4 genome AF: 0.00202 AC: 307 AN: 152284 Hom.: 11 Cov.: 32 AF XY: 0.00240 AC XY: 179 AN XY: 74450

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0447

Gnomad4 SAS AF: 0.00830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000503 Hom.: 1

Bravo AF: 0.00187

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00418 AC: 508

Asia WGS AF: 0.0300 AC: 105 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 05, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Jan 08, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Progressive familial intrahepatic cholestasis type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.0020
DANN	Benign	0.31
DEOGEN2	Benign	0.045	T;T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.47	.;T
MetaRNN	Benign	0.0015	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.94	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.060	N;.
REVEL	Benign	0.055
Sift	Benign	0.95	T;.
Sift4G	Benign	0.87	T;.
Polyphen		0.0	B;B
Vest4		0.064
MutPred		0.36		Loss of catalytic residue at M80 (P = 0.0957);Loss of catalytic residue at M80 (P = 0.0957);
MVP		0.35
ClinPred		0.0045	T
GERP RS		-12
Varity_R		0.031
gMVP		0.14

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: rs3745079; hg19: chr18-55373767; COSMIC: COSV52179979;