rs34027711

chr18-57650359-C-A

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.3531+8G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 1,611,714 control chromosomes in the GnomAD database, including 20,984 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1453 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19531 hom.)
• Consequence: ATP8B1 NM_001374385.1 splice_region, intron
• Scores: Splicing: ADA: 0.0001719
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.578

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 18-57650359-C-A is Benign according to our data. Variant chr18-57650359-C-A is described in ClinVar as [Benign]. Clinvar id is 259822.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.168 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP8B1	NM_001374385.1	c.3531+8G>T		splice_region_variant, intron_variant		ENST00000648908.2
ATP8B1-AS1	NR_164148.1	n.682+8307C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP8B1	ENST00000648908.2	c.3531+8G>T		splice_region_variant, intron_variant			NM_001374385.1	P1
	ENST00000588925.5	n.570+8307C>A		intron_variant, non_coding_transcript_variant		2
ATP8B1-AS1	ENST00000592201.1	n.663+8307C>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18489 AN: 152064 Hom.: 1453 Cov.: 32

Gnomad AFR AF: 0.0314

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.193

Gnomad EAS AF: 0.00845

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.139

GnomAD3 exomes AF: 0.140 AC: 35128 AN: 251462 Hom.: 2866 AF XY: 0.144 AC XY: 19569 AN XY: 135904

Gnomad AFR exome AF: 0.0295

Gnomad AMR exome AF: 0.141

Gnomad ASJ exome AF: 0.203

Gnomad EAS exome AF: 0.00549

Gnomad SAS exome AF: 0.137

Gnomad FIN exome AF: 0.135

Gnomad NFE exome AF: 0.172

Gnomad OTH exome AF: 0.152

GnomAD4 exome AF: 0.159 AC: 232074 AN: 1459532 Hom.: 19531 Cov.: 31 AF XY: 0.158 AC XY: 115035 AN XY: 726112

Gnomad4 AFR exome AF: 0.0256

Gnomad4 AMR exome AF: 0.144

Gnomad4 ASJ exome AF: 0.197

Gnomad4 EAS exome AF: 0.00546

Gnomad4 SAS exome AF: 0.136

Gnomad4 FIN exome AF: 0.139

Gnomad4 NFE exome AF: 0.172

Gnomad4 OTH exome AF: 0.144

GnomAD4 genome AF: 0.121 AC: 18484 AN: 152182 Hom.: 1453 Cov.: 32 AF XY: 0.120 AC XY: 8891 AN XY: 74396

Gnomad4 AFR AF: 0.0313

Gnomad4 AMR AF: 0.154

Gnomad4 ASJ AF: 0.193

Gnomad4 EAS AF: 0.00847

Gnomad4 SAS AF: 0.127

Gnomad4 FIN AF: 0.144

Gnomad4 NFE AF: 0.171

Gnomad4 OTH AF: 0.136

Alfa AF: 0.153 Hom.: 1076

Bravo AF: 0.117

Asia WGS AF: 0.0700 AC: 245 AN: 3478

EpiCase AF: 0.166

EpiControl AF: 0.169

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2015	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	PreventionGenetics, part of Exact Sciences	-	- -

Progressive familial intrahepatic cholestasis type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	7.4
Dann	Benign	0.37

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00017
dbscSNV1_RF	Benign	0.016
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.26		Position offset: -34

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs34027711; hg19: chr18-55317591;