7-138106621-C-T

Position:

chr7-138106621-C-T

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 (★★). 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

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3U: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 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
AKR1D1	NM_005989.4 linkuse as main transcript	c.593C>T	p.Pro198Leu	missense_variant	6/9	ENST00000242375.8
AKR1D1	NM_001190907.2 linkuse as main transcript	c.593C>T	p.Pro198Leu	missense_variant	6/8
AKR1D1	NM_001190906.2 linkuse as main transcript	c.470C>T	p.Pro157Leu	missense_variant	5/8
AKR1D1	XM_047420763.1 linkuse as main transcript	c.425C>T	p.Pro142Leu	missense_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKR1D1	ENST00000242375.8 linkuse as main transcript	c.593C>T	p.Pro198Leu	missense_variant	6/9	1	NM_005989.4	P1	P51857-1
AKR1D1	ENST00000432161.5 linkuse as main transcript	c.593C>T	p.Pro198Leu	missense_variant	6/8	2			P51857-2
AKR1D1	ENST00000411726.6 linkuse as main transcript	c.470C>T	p.Pro157Leu	missense_variant	5/8	2			P51857-3
AKR1D1	ENST00000468877.2 linkuse as main transcript	n.503C>T		non_coding_transcript_exon_variant	6/10	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

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251442

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135888

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 SAS exome

AF:

0.00

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

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000134

Gnomad4 OTH exome

AF:

0.000315

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

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000106

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: 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: 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

MutationTaster

Benign

1.0

A;A;A

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

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