7-138106621-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP2PP3PP5

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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P198P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

AKR1D1
NM_005989.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: 7.48

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]

AKR1D1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 6 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.17215 (below the threshold of 3.09). Trascript score misZ: 0.98686 (below the threshold of 3.09). GenCC associations: The gene is linked to congenital bile acid synthesis defect 2.

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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 5374.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKR1D1	NM_005989.4 link	c.593C>T	p.Pro198Leu	missense_variant	Exon 6 of 9	ENST00000242375.8	NP_005980.1	P51857-1
AKR1D1	NM_001190907.2 link	c.593C>T	p.Pro198Leu	missense_variant	Exon 6 of 8		NP_001177836.1	P51857-2
AKR1D1	NM_001190906.2 link	c.470C>T	p.Pro157Leu	missense_variant	Exon 5 of 8		NP_001177835.1	P51857-3
AKR1D1	XM_047420763.1 link	c.425C>T	p.Pro142Leu	missense_variant	Exon 5 of 8		XP_047276719.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AKR1D1	ENST00000242375.8 link	c.593C>T	p.Pro198Leu	missense_variant	Exon 6 of 9	1	NM_005989.4	ENSP00000242375.3	P51857-1
AKR1D1	ENST00000432161.5 link	c.593C>T	p.Pro198Leu	missense_variant	Exon 6 of 8	2		ENSP00000389197.1	P51857-2
AKR1D1	ENST00000411726.6 link	c.470C>T	p.Pro157Leu	missense_variant	Exon 5 of 8	2		ENSP00000402374.2	P51857-3
AKR1D1	ENST00000468877.2 link	n.503C>T		non_coding_transcript_exon_variant	Exon 6 of 10	2

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000176

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000278

AC:

AN:

251442

AF XY:

0.0000294

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000118

AC:

173

AN:

1461700

Hom.:

Cov.:

AF XY:

0.000114

AC XY:

AN XY:

727160

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

AC:

AN:

33470

Gnomad4 AMR exome

AF:

0.0000224

AC:

AN:

44724

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26130

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39692

Gnomad4 SAS exome

AF:

0.0000116

AC:

AN:

86250

Gnomad4 FIN exome

AF:

0.0000187

AC:

AN:

53412

Gnomad4 NFE exome

AF:

0.000134

AC:

149

AN:

1111866

Gnomad4 Remaining exome

AF:

0.000315

AC:

AN:

60390

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000483

AC:

0.0000482812

AN:

0.0000482812

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.000176

AC:

0.000176414

AN:

0.000176414

Gnomad4 OTH

AF:

0.000478

AC:

0.000478469

AN:

0.000478469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000103

Hom.:

Bravo

AF:

0.000102

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Congenital bile acid synthesis defect 2

Pathogenic:3

Jun 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The observed missense c.593C>Tp.Pro198Leu variant in AKR1D1 gene has been reported in compound heterozygous/ homozygous state in patients affected with AKR1D1 related disorderLemonde HA, et. al., 2003; Zhang MH, et. al., 2019. 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 JE, et. al., 2010. This variant is present with an allele frequency of 0.002% in gnomAD Exomes database. This variant has been submitted to the ClinVar database as Uncertain significance/ Pathogenic/ Likely pathogenic. Computational evidence Polyphen - Possibly damaging, SIFT - Tolerated and MutationTaster -Disease causing predicts conflicting evidence on protein structure and function for this variant. The amino acid change p.Pro198Leu in AKR1D1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Pro at position 198 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. Functional studies are required to prove pathogenicity of the variant. For these reasons, this variant has been classified as Likely pathogenic. -

Oct 13, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Oct 01, 2003

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1Uncertain:1

May 27, 2025

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect including decreased protein expression and stability (PMID: 20522910); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21185810, 38062451, 18243262, 33502336, 39201544, 20522910, 28215707, 30137266, 36768194, 30769091, 31222759, 30254413, 12970144, 30809085) -

Sep 23, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

.;.;T

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Benign

0.018

MetaRNN

Pathogenic

0.82

D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

M;.;M

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-6.0

D;D;D

REVEL

Uncertain

0.45

Sift

Benign

0.20

T;T;T

Sift4G

Uncertain

0.058

T;T;T

Polyphen

0.73

.;.;P

Vest4

0.91

MVP

0.62

MPC

0.54

ClinPred

0.97

GERP RS

5.0

Varity_R

0.79

gMVP

0.89

Mutation Taster

=4/96

disease causing (ClinVar)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over