18-57646765-C-T

Variant names:

• chr18-57646765-C-T
• rs11543269
• NM_001374385.1:c.*1723G>A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001374385.1(ATP8B1):​c.*1723G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0888 in 152,636 control chromosomes in the GnomAD database, including 701 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.089 (698 hom., cov: 33)
  • Exomes 𝑓: 0.11 (3 hom.)
• Consequence: ATP8B1 NM_001374385.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.65

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:56042): (ATP8B1 antisense RNA 1)

ENSG00000267787 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 18-57646765-C-T is Benign according to our data. Variant chr18-57646765-C-T is described in ClinVar as [Benign]. Clinvar id is 327441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP8B1	NM_001374385.1	c.*1723G>A		3_prime_UTR_variant	Exon 28 of 28	ENST00000648908.2	NP_001361314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP8B1	ENST00000648908	c.*1723G>A		3_prime_UTR_variant	Exon 28 of 28		NM_001374385.1	ENSP00000497896.1

Frequencies

GnomAD3 genomes AF: 0.0888 AC: 13500 AN: 152088 Hom.: 697 Cov.: 33

Gnomad AFR AF: 0.0602

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.0688

Gnomad ASJ AF: 0.0861

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0563

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.0846

GnomAD4 exome AF: 0.114 AC: 49 AN: 430 Hom.: 3 Cov.: 0 AF XY: 0.140 AC XY: 36 AN XY: 258

Gnomad4 FIN exome AF: 0.113

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0887 AC: 13499 AN: 152206 Hom.: 698 Cov.: 33 AF XY: 0.0872 AC XY: 6486 AN XY: 74416

Gnomad4 AFR AF: 0.0601

Gnomad4 AMR AF: 0.0687

Gnomad4 ASJ AF: 0.0861

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0561

Gnomad4 FIN AF: 0.107

Gnomad4 NFE AF: 0.115

Gnomad4 OTH AF: 0.0837

Alfa AF: 0.102 Hom.: 192

Bravo AF: 0.0857

Asia WGS AF: 0.0330 AC: 115 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Progressive familial intrahepatic cholestasis type 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.43
CADD	Benign	13
DANN	Benign	0.66

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: rs11543269; hg19: chr18-55313997;