18-57647234-A-G

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.*1254T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 152,204 control chromosomes in the GnomAD database, including 3,894 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.21 (3894 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: ATP8B1 NM_001374385.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.790

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=-0.87).
• BP6: Variant 18-57647234-A-G is Benign according to our data. Variant chr18-57647234-A-G is described in ClinVar as [Benign]. Clinvar id is 327445.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.271 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP8B1	NM_001374385.1	c.*1254T>C		3_prime_UTR_variant	28/28	ENST00000648908.2
ATP8B1-AS1	NR_164148.1	n.682+5182A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP8B1	ENST00000648908.2	c.*1254T>C		3_prime_UTR_variant	28/28		NM_001374385.1	P1
	ENST00000588925.5	n.570+5182A>G		intron_variant, non_coding_transcript_variant		2
ATP8B1-AS1	ENST00000592201.1	n.663+5182A>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31196 AN: 152086 Hom.: 3894 Cov.: 33

Gnomad AFR AF: 0.0881

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.206

Gnomad ASJ AF: 0.271

Gnomad EAS AF: 0.0159

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.295

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.275

Gnomad OTH AF: 0.233

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.205 AC: 31203 AN: 152204 Hom.: 3894 Cov.: 33 AF XY: 0.203 AC XY: 15082 AN XY: 74416

Gnomad4 AFR AF: 0.0881

Gnomad4 AMR AF: 0.206

Gnomad4 ASJ AF: 0.271

Gnomad4 EAS AF: 0.0160

Gnomad4 SAS AF: 0.194

Gnomad4 FIN AF: 0.295

Gnomad4 NFE AF: 0.275

Gnomad4 OTH AF: 0.229

Alfa AF: 0.241 Hom.: 2016

Bravo AF: 0.190

Asia WGS AF: 0.112 AC: 391 AN: 3476

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	-0.87
Cadd	Benign	1.5
Dann	Benign	0.65

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: rs17685852; hg19: chr18-55314466;