rs121918342
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_005989.4(AKR1D1):c.593C>T(p.Pro198Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,613,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000099 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00012 ( 0 hom. )
Consequence
AKR1D1
NM_005989.4 missense
NM_005989.4 missense
Scores
3
11
4
Clinical Significance
Conservation
PhyloP100: 7.48
Genes affected
AKR1D1 (HGNC:388): (aldo-keto reductase family 1 member D1) The enzyme encoded by this gene is responsible for the catalysis of the 5-beta-reduction of bile acid intermediates and steroid hormones carrying a delta(4)-3-one structure. Deficiency of this enzyme may contribute to hepatic dysfunction. Three transcript variants encoding different isoforms have been found for this gene. Other variants may be present, but their full-length natures have not been determined yet. [provided by RefSeq, Jul 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.824
PP5
?
Variant 7-138106621-C-T is Pathogenic according to our data. Variant chr7-138106621-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AKR1D1 | NM_005989.4 | c.593C>T | p.Pro198Leu | missense_variant | 6/9 | ENST00000242375.8 | |
AKR1D1 | NM_001190907.2 | c.593C>T | p.Pro198Leu | missense_variant | 6/8 | ||
AKR1D1 | NM_001190906.2 | c.470C>T | p.Pro157Leu | missense_variant | 5/8 | ||
AKR1D1 | XM_047420763.1 | c.425C>T | p.Pro142Leu | missense_variant | 5/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AKR1D1 | ENST00000242375.8 | c.593C>T | p.Pro198Leu | missense_variant | 6/9 | 1 | NM_005989.4 | P1 | |
AKR1D1 | ENST00000432161.5 | c.593C>T | p.Pro198Leu | missense_variant | 6/8 | 2 | |||
AKR1D1 | ENST00000411726.6 | c.470C>T | p.Pro157Leu | missense_variant | 5/8 | 2 | |||
AKR1D1 | ENST00000468877.2 | n.503C>T | non_coding_transcript_exon_variant | 6/10 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000986 AC: 15AN: 152138Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251442Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135888
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GnomAD4 exome AF: 0.000118 AC: 173AN: 1461700Hom.: 0 Cov.: 31 AF XY: 0.000114 AC XY: 83AN XY: 727160
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GnomAD4 genome ? AF: 0.0000986 AC: 15AN: 152138Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6AN XY: 74330
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Congenital bile acid synthesis defect 2 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 13, 2023 | Variant summary: AKR1D1 c.593C>T (p.Pro198Leu) results in a non-conservative amino acid change located in the NADP-dependent oxidoreductase domain (IPR023210) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251442 control chromosomes (gnomAD). c.593C>T has been reported in the literature in individuals affected with neonatal onset cholestatic/AKR1D1 deficiency (examples: Lemonde_2003, Palmero_2008, Zhang_2019, Wang_2019). These data indicate that the variant may be associated with disease. Multiple studies have shown mutant P198L showed reduced protein expression and decreased protein stability compared to wild type, as well as displayed no detectable 5b-reductase enzyme activity using testosterone as a substrate (examples: Drury_2010 and Mindnich_2011). The following publications have been ascertained in the context of this evaluation (PMID: 12970144, 30809085, 31450232, 21185810, 18243262, 20522910). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2003 | - - |
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 09, 2016 | The P198L variant in the AKR1D1 gene has been reported previously in the homozygous state in an individual with neonatal onset cholestatic liver disease (Lemonde et al., 2003). HEK293 cells transiently transfected with the P198L variant showed reduced protein expression and decreased protein stability compared to wild type, as well as displayed no detectable 5b-reductase enzyme activity using testosterone as substrate (Drury et al., 2010). The P198L variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P198L variant is a semi-conservative amino acid substitution, which occurs at a position that is conserved across species. The P198L variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. - |
Uncertain significance, flagged submission | clinical testing | Eurofins Ntd Llc (ga) | Sep 23, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
T
MetaRNN
Pathogenic
D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.;M
MutationTaster
Benign
A;A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Uncertain
Sift
Benign
T;T;T
Sift4G
Uncertain
T;T;T
Polyphen
0.73
.;.;P
Vest4
MVP
MPC
0.54
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at