18-57646548-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_001374385.1(ATP8B1):c.*1940A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0049 in 152,778 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0049 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0047 (0 hom.)
• Consequence: ATP8B1 NM_001374385.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.687

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 18-57646548-T-C is Benign according to our data. Variant chr18-57646548-T-C is described in ClinVar as [Benign]. Clinvar id is 327439.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0049 (746/152350) while in subpopulation EAS AF= 0.0439 (228/5190). AF 95% confidence interval is 0.0393. There are 9 homozygotes in gnomad4. There are 410 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP8B1	NM_001374385.1	c.*1940A>G		3_prime_UTR_variant	28/28	ENST00000648908.2
ATP8B1-AS1	NR_164148.1	n.682+4496T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP8B1	ENST00000648908.2	c.*1940A>G		3_prime_UTR_variant	28/28		NM_001374385.1	P1
	ENST00000588925.5	n.570+4496T>C		intron_variant, non_coding_transcript_variant		2
ATP8B1-AS1	ENST00000592201.1	n.663+4496T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00489 AC: 745 AN: 152232 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0205

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0442

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00184

Gnomad OTH AF: 0.0105

GnomAD4 exome AF: 0.00467 AC: 2 AN: 428 Hom.: 0 Cov.: 0 AF XY: 0.00781 AC XY: 2 AN XY: 256

Gnomad4 FIN exome AF: 0.00474

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00490 AC: 746 AN: 152350 Hom.: 9 Cov.: 33 AF XY: 0.00550 AC XY: 410 AN XY: 74500

Gnomad4 AFR AF: 0.000625

Gnomad4 AMR AF: 0.0208

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.0439

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00184

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00391 Hom.: 0

Bravo AF: 0.00681

Asia WGS AF: 0.0120 AC: 43 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	-0.28
Cadd	Benign	13
Dann	Benign	0.85

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: rs117693241; hg19: chr18-55313780;