10-5099435-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_003739.6(AKR1C3):​c.556C>T​(p.Pro186Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

AKR1C3
NM_003739.6 missense

Scores

5
8
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.72
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.975

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AKR1C3NM_003739.6 linkc.556C>T p.Pro186Ser missense_variant Exon 5 of 9 ENST00000380554.5 NP_003730.4 P42330-1
AKR1C3NM_001253908.2 linkc.556C>T p.Pro186Ser missense_variant Exon 5 of 9 NP_001240837.1 P42330A0A0A0MSS8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AKR1C3ENST00000380554.5 linkc.556C>T p.Pro186Ser missense_variant Exon 5 of 9 1 NM_003739.6 ENSP00000369927.3 P42330-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 10, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.556C>T (p.P186S) alteration is located in exon 5 (coding exon 5) of the AKR1C3 gene. This alteration results from a C to T substitution at nucleotide position 556, causing the proline (P) at amino acid position 186 to be replaced by a serine (S). 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
0.93
BayesDel_addAF
Uncertain
0.031
T
BayesDel_noAF
Benign
-0.19
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.17
.;T;T
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Uncertain
0.92
D;D;D
M_CAP
Benign
0.014
T
MetaRNN
Pathogenic
0.98
D;D;D
MetaSVM
Benign
-0.60
T
MutationAssessor
Pathogenic
3.9
.;.;H
PrimateAI
Benign
0.39
T
PROVEAN
Pathogenic
-7.9
.;.;D
REVEL
Uncertain
0.33
Sift
Pathogenic
0.0
.;.;D
Sift4G
Uncertain
0.0080
D;D;D
Polyphen
1.0
.;.;D
Vest4
0.87
MutPred
0.91
Loss of methylation at K183 (P = 0.0526);.;Loss of methylation at K183 (P = 0.0526);
MVP
0.49
MPC
0.080
ClinPred
1.0
D
GERP RS
2.7
Varity_R
0.99
gMVP
0.78

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-5141627; API