chr7-138107506-C-T

Position:

chr7-138107506-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_005989.4(AKR1D1):c.781C>T(p.Arg261Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000372 in 1,613,972 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 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

AKR1D1
NM_005989.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 4.47

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:

AKR1D1 (HGNC:):

AKR1D1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

PP5

Variant 7-138107506-C-T is Pathogenic according to our data. Variant chr7-138107506-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5378.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 linkuse as main transcript	c.781C>T	p.Arg261Cys	missense_variant	7/9	ENST00000242375.8	NP_005980.1	P51857-1
AKR1D1	NM_001190907.2 linkuse as main transcript	c.781C>T	p.Arg261Cys	missense_variant	7/8		NP_001177836.1	P51857-2
AKR1D1	NM_001190906.2 linkuse as main transcript	c.658C>T	p.Arg220Cys	missense_variant	6/8		NP_001177835.1	P51857-3
AKR1D1	XM_047420763.1 linkuse as main transcript	c.613C>T	p.Arg205Cys	missense_variant	6/8		XP_047276719.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AKR1D1	ENST00000242375.8 linkuse as main transcript	c.781C>T	p.Arg261Cys	missense_variant	7/9	1	NM_005989.4	ENSP00000242375.3	P51857-1
AKR1D1	ENST00000432161.5 linkuse as main transcript	c.781C>T	p.Arg261Cys	missense_variant	7/8	2		ENSP00000389197.1	P51857-2
AKR1D1	ENST00000411726.6 linkuse as main transcript	c.658C>T	p.Arg220Cys	missense_variant	6/8	2		ENSP00000402374.2	P51857-3
AKR1D1	ENST00000468877.2 linkuse as main transcript	n.804C>T		non_coding_transcript_exon_variant	8/10	2

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152128

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251400

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000376

AC:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

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:

0.0000432

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74322

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000680

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital bile acid synthesis defect 2

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 09, 2024	Variant summary: AKR1D1 c.781C>T (p.Arg261Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251400 control chromosomes (gnomAD). c.781C>T has been reported in the literature in individuals affected with Congenital bile acid synthesis defect 2 (e.g. Gonzales_2004, Seki_2013). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in sharpy reduced enzymatic activity (Drury_2010). The following publications have been ascertained in the context of this evaluation (PMID: 15030995, 20522910, 23160874). ClinVar contains an entry for this variant (Variation ID: 5378). Based on the evidence outlined above, the variant was classified as pathogenic. -

Congenital bile acid synthesis defect

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Oct 04, 2024

PS3,PM2,PP3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.32

.;.;T

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Uncertain

-0.25

MutationAssessor

Uncertain

2.7

M;.;M

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-6.7

D;D;D

REVEL

Uncertain

0.60

Sift

Uncertain

0.016

D;D;D

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

1.0

.;.;D

Vest4

0.94

MutPred

0.94

Loss of MoRF binding (P = 0.0051);.;Loss of MoRF binding (P = 0.0051);

MVP

0.70

MPC

0.64

ClinPred

1.0

GERP RS

5.5

Varity_R

0.91

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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