rs117182648

chr18-57650421-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001374385.1(ATP8B1):c.3477C>T(p.Pro1159=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,613,930 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (64 hom.)
• Consequence: ATP8B1 NM_001374385.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.503

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:):

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

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 18-57650421-G-A is Benign according to our data. Variant chr18-57650421-G-A is described in ClinVar as [Benign]. Clinvar id is 259821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.503 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00194 (296/152274) while in subpopulation EAS AF= 0.0452 (234/5180). AF 95% confidence interval is 0.0404. There are 10 homozygotes in gnomad4. There are 174 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP8B1	NM_001374385.1	c.3477C>T	p.Pro1159=	synonymous_variant	27/28	ENST00000648908.2
ATP8B1-AS1	NR_164148.1	n.682+8369G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP8B1	ENST00000648908.2	c.3477C>T	p.Pro1159=	synonymous_variant	27/28		NM_001374385.1	P1
	ENST00000588925.5	n.570+8369G>A		intron_variant, non_coding_transcript_variant		2
ATP8B1-AS1	ENST00000592201.1	n.663+8369G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00195 AC: 297 AN: 152156 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0453

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00401 AC: 1008 AN: 251488 Hom.: 26 AF XY: 0.00374 AC XY: 508 AN XY: 135922

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0485

Gnomad SAS exome AF: 0.00255

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00171 AC: 2502 AN: 1461656 Hom.: 64 Cov.: 31 AF XY: 0.00175 AC XY: 1269 AN XY: 727138

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0508

Gnomad4 SAS exome AF: 0.00249

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000944

Gnomad4 OTH exome AF: 0.00205

GnomAD4 genome AF: 0.00194 AC: 296 AN: 152274 Hom.: 10 Cov.: 32 AF XY: 0.00234 AC XY: 174 AN XY: 74448

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0452

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.000429 Hom.: 1

Bravo AF: 0.00194

Asia WGS AF: 0.0320 AC: 111 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 05, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 16, 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:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

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
BayesDel_noAF	Benign	-0.46
Cadd	Benign	1.5
Dann	Benign	0.50

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: rs117182648; hg19: chr18-55317653; COSMIC: COSV52176682;