rs121918342

Positions:

• chr7-138106621-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_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 (★★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: AKR1D1 NM_005989.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• Conservation: PhyloP100: 7.48

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 (HGNC:):

ACMG classification

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	Protein	UniProt
AKR1D1	NM_005989.4	c.593C>T	p.Pro198Leu	missense_variant	6/9	ENST00000242375.8	NP_005980.1
AKR1D1	NM_001190907.2	c.593C>T	p.Pro198Leu	missense_variant	6/8		NP_001177836.1
AKR1D1	NM_001190906.2	c.470C>T	p.Pro157Leu	missense_variant	5/8		NP_001177835.1
AKR1D1	XM_047420763.1	c.425C>T	p.Pro142Leu	missense_variant	5/8		XP_047276719.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKR1D1	ENST00000242375.8	c.593C>T	p.Pro198Leu	missense_variant	6/9	1	NM_005989.4	ENSP00000242375.3
AKR1D1	ENST00000432161.5	c.593C>T	p.Pro198Leu	missense_variant	6/8	2		ENSP00000389197.1
AKR1D1	ENST00000411726.6	c.470C>T	p.Pro157Leu	missense_variant	5/8	2		ENSP00000402374.2
AKR1D1	ENST00000468877.2	n.503C>T		non_coding_transcript_exon_variant	6/10	2

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152138 Hom.: 0 Cov.: 33

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: 7 AN: 251442 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135888

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.: 0 Cov.: 31 AF XY: 0.000114 AC XY: 83 AN XY: 727160

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: 15 AN: 152138 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74330

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.: 0

Bravo AF: 0.000102

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital bile acid synthesis defect 2 Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2003	- -
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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Jun 22, 2023	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. -

not provided Pathogenic:1 Uncertain:1

Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Sep 23, 2016	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	.;.;T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;.;M
PrimateAI	Uncertain	0.74	T
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	D
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

Other links and lift over

dbSNP: rs121918342; hg19: chr7-137791367; COSMIC: COSV54336966;