18-57647588-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001374385.1(ATP8B1):c.*900G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.461 in 152,300 control chromosomes in the GnomAD database, including 16,519 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.46 (16451 hom., cov: 32)
  • Exomes 𝑓: 0.57 (68 hom.)
• Consequence: ATP8B1 NM_001374385.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0270

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 18-57647588-C-A is Benign according to our data. Variant chr18-57647588-C-A is described in ClinVar as [Benign]. Clinvar id is 327449.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.502 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP8B1	NM_001374385.1	c.*900G>T		3_prime_UTR_variant	28/28	ENST00000648908.2
ATP8B1-AS1	NR_164148.1	n.682+5536C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP8B1	ENST00000648908.2	c.*900G>T		3_prime_UTR_variant	28/28		NM_001374385.1	P1
	ENST00000588925.5	n.570+5536C>A		intron_variant, non_coding_transcript_variant		2
ATP8B1-AS1	ENST00000592201.1	n.663+5536C>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.460 AC: 69859 AN: 151764 Hom.: 16439 Cov.: 32

Gnomad AFR AF: 0.379

Gnomad AMI AF: 0.522

Gnomad AMR AF: 0.509

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.519

Gnomad SAS AF: 0.440

Gnomad FIN AF: 0.562

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.479

Gnomad OTH AF: 0.479

GnomAD4 exome AF: 0.574 AC: 240 AN: 418 Hom.: 68 Cov.: 0 AF XY: 0.601 AC XY: 149 AN XY: 248

Gnomad4 FIN exome AF: 0.575

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.460 AC: 69912 AN: 151882 Hom.: 16451 Cov.: 32 AF XY: 0.464 AC XY: 34453 AN XY: 74234

Gnomad4 AFR AF: 0.379

Gnomad4 AMR AF: 0.509

Gnomad4 ASJ AF: 0.461

Gnomad4 EAS AF: 0.519

Gnomad4 SAS AF: 0.440

Gnomad4 FIN AF: 0.562

Gnomad4 NFE AF: 0.479

Gnomad4 OTH AF: 0.480

Alfa AF: 0.406 Hom.: 2232

Bravo AF: 0.456

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Progressive familial intrahepatic cholestasis type 1 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	1.3
Dann	Benign	0.34

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: rs4940950; hg19: chr18-55314820; COSMIC: COSV52181574;