18-57695198-A-T
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2
The NM_001374385.1(ATP8B1):c.913T>A(p.Phe305Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,614,202 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001374385.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP8B1 | NM_001374385.1 | c.913T>A | p.Phe305Ile | missense_variant | 10/28 | ENST00000648908.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP8B1 | ENST00000648908.2 | c.913T>A | p.Phe305Ile | missense_variant | 10/28 | NM_001374385.1 | P1 | ||
ENST00000588925.5 | n.571-36216A>T | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes AF: 0.00118 AC: 180AN: 152228Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00118 AC: 296AN: 251422Hom.: 0 AF XY: 0.00118 AC XY: 161AN XY: 135914
GnomAD4 exome AF: 0.00184 AC: 2691AN: 1461856Hom.: 8 Cov.: 32 AF XY: 0.00172 AC XY: 1254AN XY: 727222
GnomAD4 genome AF: 0.00118 AC: 180AN: 152346Hom.: 0 Cov.: 32 AF XY: 0.00109 AC XY: 81AN XY: 74500
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:3
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 21, 2024 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in the heterozygous state in individuals with intrahepatic cholestasis of pregnancy, chronic pancreatitis, or cryptogenic cholestasis in whom a second variant in ATP8B1 was not identified. This variant was also identified in multiple healthy control individuals (PMID: 15888793, 24260417, 29238877); This variant is associated with the following publications: (PMID: Barkaoui[Article]2018, 33666275, 24260417, 29238877, 28733223, 34679599, 15888793) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2016 | - - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 18, 2022 | Variant summary: ATP8B1 c.913T>A (p.Phe305Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 251422 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATP8B1 causing Familial Intrahepatic Cholestasis (0.0012 vs 0.0022), allowing no conclusion about variant significance. c.913T>A has been reported in the literature in individuals affected with intrahepatic cholestasis of pregnancy (Mullenbach_2005) or FIC1 deficiency (van Wessel_2021). These reports do not provide unequivocal conclusions about association of the variant with Familial Intrahepatic Cholestasis. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign n=1, VUS n=3). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 15, 2016 | - - |
ATP8B1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 02, 2024 | The ATP8B1 c.913T>A variant is predicted to result in the amino acid substitution p.Phe305Ile. This variant has been reported in patients with ATP8B1-related disease, including PFIC, cryptogenic cholestasis, intrahepatic cholestasis of pregnancy, and chronic pancreatitis (Müllenbach et al. 2005. PubMed ID: 15888793; van der Woerd et al. 2013. PubMed ID: 24260417; Dröge et al. 2017. PubMed ID: 28733223; Vitale et al. 2018. PubMed ID: 29238877). However, this variant has also been documented in healthy controls (Müllenbach et al. 2005. PubMed ID: 15888793; Woerd et al. 2013. PubMed ID: 24260417). This variant is found at an allele frequency of up to 0.42% in individuals of Ashkenazi Jewish descent in gnomAD. Recently, 8 homozygotes, mostly in individuals of European descent, have been identified in the gnomAD V4 dataset. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Progressive familial intrahepatic cholestasis type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at