10-5099435-C-T

Variant names:

• chr10-5099435-C-T
• NM_003739.6:c.556C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.72

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]

ACMG classification

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
AKR1C3	NM_003739.6	c.556C>T	p.Pro186Ser	missense_variant	Exon 5 of 9	ENST00000380554.5	NP_003730.4
AKR1C3	NM_001253908.2	c.556C>T	p.Pro186Ser	missense_variant	Exon 5 of 9		NP_001240837.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKR1C3	ENST00000380554.5	c.556C>T	p.Pro186Ser	missense_variant	Exon 5 of 9	1	NM_003739.6	ENSP00000369927.3

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

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;