rs267606649
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_005989.4(AKR1D1):c.398C>A(p.Pro133His) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,606,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.
Frequency
Genomes: 𝑓 0.0000067 ( 0 hom., cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
AKR1D1
NM_005989.4 missense
NM_005989.4 missense
Scores
5
11
3
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 7.12
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 Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.984
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AKR1D1 | NM_005989.4 | c.398C>A | p.Pro133His | missense_variant | 4/9 | ENST00000242375.8 | NP_005980.1 | |
AKR1D1 | NM_001190907.2 | c.398C>A | p.Pro133His | missense_variant | 4/8 | NP_001177836.1 | ||
AKR1D1 | NM_001190906.2 | c.398C>A | p.Pro133His | missense_variant | 4/8 | NP_001177835.1 | ||
AKR1D1 | XM_047420763.1 | c.230C>A | p.Pro77His | missense_variant | 3/8 | XP_047276719.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AKR1D1 | ENST00000242375.8 | c.398C>A | p.Pro133His | missense_variant | 4/9 | 1 | NM_005989.4 | ENSP00000242375 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000673 AC: 1AN: 148594Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1457876Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 725506
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GnomAD4 genome AF: 0.00000673 AC: 1AN: 148594Hom.: 0 Cov.: 32 AF XY: 0.0000139 AC XY: 1AN XY: 71980
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ClinVar
Not reported inComputational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
.;.;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Benign
T
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;M;M;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D
REVEL
Uncertain
Sift
Pathogenic
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
1.0
.;.;D;.
Vest4
MutPred
Loss of catalytic residue at P133 (P = 0.0247);Loss of catalytic residue at P133 (P = 0.0247);Loss of catalytic residue at P133 (P = 0.0247);.;
MVP
MPC
0.59
ClinPred
D
GERP RS
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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