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

Scores

5
11
3

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.12
Variant links:
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]

Genome browser will be placed here

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
AKR1D1NM_005989.4 linkuse as main transcriptc.398C>A p.Pro133His missense_variant 4/9 ENST00000242375.8 NP_005980.1
AKR1D1NM_001190907.2 linkuse as main transcriptc.398C>A p.Pro133His missense_variant 4/8 NP_001177836.1
AKR1D1NM_001190906.2 linkuse as main transcriptc.398C>A p.Pro133His missense_variant 4/8 NP_001177835.1
AKR1D1XM_047420763.1 linkuse as main transcriptc.230C>A p.Pro77His missense_variant 3/8 XP_047276719.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AKR1D1ENST00000242375.8 linkuse as main transcriptc.398C>A p.Pro133His missense_variant 4/91 NM_005989.4 ENSP00000242375 P1P51857-1

Frequencies

GnomAD3 genomes
AF:
0.00000673
AC:
1
AN:
148594
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000673
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
6.86e-7
AC:
1
AN:
1457876
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
725506
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000673
AC:
1
AN:
148594
Hom.:
0
Cov.:
32
AF XY:
0.0000139
AC XY:
1
AN XY:
71980
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000673
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.76
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Uncertain
-0.030
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Benign
0.25
.;.;T;T
Eigen
Uncertain
0.65
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.92
D;D;D;D
M_CAP
Benign
0.024
T
MetaRNN
Pathogenic
0.98
D;D;D;D
MetaSVM
Uncertain
-0.11
T
MutationAssessor
Uncertain
2.8
M;M;M;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.49
T
PROVEAN
Pathogenic
-8.3
D;D;D;D
REVEL
Uncertain
0.54
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Uncertain
0.015
D;D;D;D
Polyphen
1.0
.;.;D;.
Vest4
0.85
MutPred
0.94
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
0.81
MPC
0.59
ClinPred
1.0
D
GERP RS
5.1
Varity_R
0.95
gMVP
0.70

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs267606649; hg19: chr7-137782631; API