Variant 10-5102485-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_003739.6(AKR1C3):c.681G>T(p.Trp227Cys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 28)

Failed GnomAD Quality Control

Consequence

AKR1C3
NM_003739.6 missense, splice_region

Scores

Splicing: ADA: 0.04147

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.83

Variant links:

Genes affected

AKR1C3 (HGNC:386): (aldo-keto reductase family 1 member C3) This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. These enzymes catalyze the conversion of aldehydes and ketones to their corresponding alcohols by utilizing NADH and/or NADPH as cofactors. The enzymes display overlapping but distinct substrate specificity. This enzyme catalyzes the reduction of prostaglandin (PG) D2, PGH2 and phenanthrenequinone (PQ), and the oxidation of 9alpha,11beta-PGF2 to PGD2. It may play an important role in the pathogenesis of allergic diseases such as asthma, and may also have a role in controlling cell growth and/or differentiation. This gene shares high sequence identity with three other gene members and is clustered with those three genes at chromosome 10p15-p14. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

AKR1C3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a site Involved in ligand recognition and product release (size 0) in uniprot entity AK1C3_HUMAN

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKR1C3	NM_003739.6 linkuse as main transcript	c.681G>T	p.Trp227Cys	missense_variant, splice_region_variant	7/9	ENST00000380554.5
AKR1C3	NM_001253908.2 linkuse as main transcript	c.681G>T	p.Trp227Cys	missense_variant, splice_region_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKR1C3	ENST00000380554.5 linkuse as main transcript	c.681G>T	p.Trp227Cys	missense_variant, splice_region_variant	7/9	1	NM_003739.6	P4	P42330-1
AKR1C3	ENST00000439082.7 linkuse as main transcript	c.681G>T	p.Trp227Cys	missense_variant, splice_region_variant	7/9	5		A1
AKR1C3	ENST00000605149.5 linkuse as main transcript	c.612G>T	p.Trp204Cys	missense_variant, splice_region_variant	7/9	2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

151480

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000660

AC:

AN:

151480

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73920

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2023

The c.681G>T (p.W227C) alteration is located in exon 7 (coding exon 7) of the AKR1C3 gene. This alteration results from a G to T substitution at nucleotide position 681, causing the tryptophan (W) at amino acid position 227 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.067

.;T;T

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.41

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Benign

0.0081

MetaRNN

Uncertain

0.45

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

.;.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-10

.;.;D

REVEL

Benign

0.18

Sift

Benign

0.033

.;.;D

Sift4G

Uncertain

0.013

D;D;D

Polyphen

0.40

.;.;B

Vest4

0.43

MutPred

0.59

Loss of catalytic residue at P230 (P = 0.0267);.;Loss of catalytic residue at P230 (P = 0.0267);

MVP

0.31

MPC

0.029

ClinPred

0.95

GERP RS

1.0

Varity_R

0.66

gMVP

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.041

dbscSNV1_RF

Benign

0.40

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