Genetic Variant AKR1D1:p.Pro198Leu (chr7-138106621-C-T) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS3PP2PP3PP5

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). ClinVar reports functional evidence for this variant: "SCV004122873: 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). PMID:12970144, 30809085, 31450232, 21185810, 18243262, 20522910" and additional evidence is available in ClinVar. 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:5U:1

Conservation

PhyloP100: 7.48

Publications

25 publications found

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 Gene-Disease associations (from GenCC):

congenital bile acid synthesis defect 2
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

AKR1D1 links:

ENSG00000308006 (HGNC:):

ENSG00000308006 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV004122873: 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). PMID: 12970144, 30809085, 31450232, 21185810, 18243262, 20522910; SCV005439086: 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.; SCV006301672: Functional studies support its pathogenicity (Lemonde et al 2003. PubMed ID: 12970144; Palermo M et al 2007. PubMed ID: 18243262; Drury JE et al 2010. PubMed ID: 20522910; Mindnich R et al 2010. PubMed ID: 21185810).; SCV000521347: Published functional studies demonstrate a damaging effect including decreased protein expression and stability (PMID: 20522910);

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 VariationId is 5374.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005989.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AKR1D1	NM_005989.4	MANE Select	c.593C>T	p.Pro198Leu	missense	Exon 6 of 9	NP_005980.1	P51857-1
AKR1D1	NM_001190907.2		c.593C>T	p.Pro198Leu	missense	Exon 6 of 8	NP_001177836.1	P51857-2
AKR1D1	NM_001190906.2		c.470C>T	p.Pro157Leu	missense	Exon 5 of 8	NP_001177835.1	P51857-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AKR1D1	ENST00000242375.8	TSL:1 MANE Select	c.593C>T	p.Pro198Leu	missense	Exon 6 of 9	ENSP00000242375.3	P51857-1
AKR1D1	ENST00000885436.1		c.722C>T	p.Pro241Leu	missense	Exon 8 of 11	ENSP00000555495.1
AKR1D1	ENST00000885435.1		c.593C>T	p.Pro198Leu	missense	Exon 7 of 10	ENSP00000555494.1

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

African (AFR)

AF:

0.0000598

AC:

AN:

33470

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000134

AC:

149

AN:

1111866

Other (OTH)

AF:

0.000315

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

African (AFR)

AF:

0.0000483

AC:

AN:

41424

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68022

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital bile acid synthesis defect 2 (4)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.018

MetaRNN

Pathogenic

0.82

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

PhyloP100

7.5

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-6.0

REVEL

Uncertain

0.45

Sift

Benign

0.20

Sift4G

Uncertain

0.058

Polyphen

0.73

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)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over