rs121918343

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5

The NM_005989.4(AKR1D1):c.316C>T(p.Leu106Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,840 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 Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

AKR1D1
NM_005989.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 2.03

Publications

14 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: Labcorp Genetics (formerly Invitae), G2P, 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 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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, 0.98

PP5

Variant 7-138091822-C-T is Pathogenic according to our data. Variant chr7-138091822-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 5376.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKR1D1	NM_005989.4 link	c.316C>T	p.Leu106Phe	missense_variant	Exon 3 of 9	ENST00000242375.8	NP_005980.1	P51857-1
AKR1D1	NM_001190907.2 link	c.316C>T	p.Leu106Phe	missense_variant	Exon 3 of 8		NP_001177836.1	P51857-2
AKR1D1	NM_001190906.2 link	c.316C>T	p.Leu106Phe	missense_variant	Exon 3 of 8		NP_001177835.1	P51857-3
AKR1D1	XM_047420763.1 link	c.148C>T	p.Leu50Phe	missense_variant	Exon 2 of 8		XP_047276719.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKR1D1	ENST00000242375.8 link	c.316C>T	p.Leu106Phe	missense_variant	Exon 3 of 9	1	NM_005989.4	ENSP00000242375.3		P51857-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251438

AF XY:

0.00000736

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461840

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111970

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000654

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Congenital bile acid synthesis defect 2

Pathogenic:1

Oct 01, 2003

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.35

.;.;T;T

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.94

D;D;D;D

M_CAP

Benign

0.035

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Uncertain

0.27

MutationAssessor

Pathogenic

3.1

M;M;M;.

PhyloP100

2.0

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.8

D;D;D;D

REVEL

Uncertain

0.48

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Uncertain

0.0090

D;D;D;D

Polyphen

1.0

.;.;D;.

Vest4

0.88

MutPred

0.95

Loss of stability (P = 0.1791);Loss of stability (P = 0.1791);Loss of stability (P = 0.1791);.;

MVP

0.85

MPC

0.57

ClinPred

0.99

GERP RS

5.3

Varity_R

0.97

gMVP

0.82

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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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rs121918343

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over