rs12958967

Positions:

• chr18-57648727-G-A
• chr18-57648727-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001374385.1(ATP8B1):​c.3532-15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 1,548,334 control chromosomes in the GnomAD database, including 50,815 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3745 hom., cov: 32)
  • Exomes 𝑓: 0.25 (47070 hom.)
• Consequence: ATP8B1 NM_001374385.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.271

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]

ATP8B1-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 18-57648727-G-A is Benign according to our data. Variant chr18-57648727-G-A is described in ClinVar as [Benign]. Clinvar id is 259823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-57648727-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP8B1	NM_001374385.1	c.3532-15C>T		intron_variant		ENST00000648908.2	NP_001361314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP8B1	ENST00000648908.2	c.3532-15C>T		intron_variant			NM_001374385.1	ENSP00000497896.1

Frequencies

GnomAD3 genomes AF: 0.198 AC: 30028 AN: 151812 Hom.: 3745 Cov.: 32

Gnomad AFR AF: 0.0655

Gnomad AMI AF: 0.0749

Gnomad AMR AF: 0.204

Gnomad ASJ AF: 0.271

Gnomad EAS AF: 0.0161

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.294

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.228

GnomAD3 exomes AF: 0.217 AC: 32134 AN: 148126 Hom.: 4000 AF XY: 0.221 AC XY: 17381 AN XY: 78598

Gnomad AFR exome AF: 0.0629

Gnomad AMR exome AF: 0.189

Gnomad ASJ exome AF: 0.279

Gnomad EAS exome AF: 0.00963

Gnomad SAS exome AF: 0.210

Gnomad FIN exome AF: 0.277

Gnomad NFE exome AF: 0.270

Gnomad OTH exome AF: 0.244

GnomAD4 exome AF: 0.253 AC: 353833 AN: 1396404 Hom.: 47070 Cov.: 33 AF XY: 0.252 AC XY: 173556 AN XY: 688616

Gnomad4 AFR exome AF: 0.0582

Gnomad4 AMR exome AF: 0.193

Gnomad4 ASJ exome AF: 0.272

Gnomad4 EAS exome AF: 0.00787

Gnomad4 SAS exome AF: 0.208

Gnomad4 FIN exome AF: 0.277

Gnomad4 NFE exome AF: 0.272

Gnomad4 OTH exome AF: 0.231

GnomAD4 genome AF: 0.198 AC: 30032 AN: 151930 Hom.: 3745 Cov.: 32 AF XY: 0.196 AC XY: 14542 AN XY: 74252

Gnomad4 AFR AF: 0.0655

Gnomad4 AMR AF: 0.204

Gnomad4 ASJ AF: 0.271

Gnomad4 EAS AF: 0.0161

Gnomad4 SAS AF: 0.193

Gnomad4 FIN AF: 0.294

Gnomad4 NFE AF: 0.273

Gnomad4 OTH AF: 0.224

Alfa AF: 0.252 Hom.: 8958

Bravo AF: 0.182

Asia WGS AF: 0.112 AC: 389 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 25, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

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

Progressive familial intrahepatic cholestasis type 1 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Cholestasis, intrahepatic, of pregnancy, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.9
DANN	Benign	0.41

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: rs12958967; hg19: chr18-55315959;