rs12529

Positions:

• chr10-5094459-C-G
• chr10-5094459-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003739.6(AKR1C3):​c.15C>G​(p.His5Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.435 in 1,611,454 control chromosomes in the GnomAD database, including 162,669 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.46 (16664 hom., cov: 31)
  • Exomes 𝑓: 0.43 (146005 hom.)
• Consequence: AKR1C3 NM_003739.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.22

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.4115163E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.839 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKR1C3	NM_003739.6	c.15C>G	p.His5Gln	missense_variant	1/9	ENST00000380554.5
AKR1C3	NM_001253909.2	c.15C>G	p.His5Gln	missense_variant	1/3
AKR1C3	NM_001253908.2	c.85-1951C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKR1C3	ENST00000380554.5	c.15C>G	p.His5Gln	missense_variant	1/9	1	NM_003739.6	P4

Frequencies

GnomAD3 genomes AF: 0.456 AC: 69127 AN: 151702 Hom.: 16647 Cov.: 31

Gnomad AFR AF: 0.474

Gnomad AMI AF: 0.474

Gnomad AMR AF: 0.502

Gnomad ASJ AF: 0.596

Gnomad EAS AF: 0.860

Gnomad SAS AF: 0.647

Gnomad FIN AF: 0.329

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.399

Gnomad OTH AF: 0.521

GnomAD3 exomes AF: 0.501 AC: 125720 AN: 251128 Hom.: 34101 AF XY: 0.501 AC XY: 68038 AN XY: 135718

Gnomad AFR exome AF: 0.472

Gnomad AMR exome AF: 0.599

Gnomad ASJ exome AF: 0.589

Gnomad EAS exome AF: 0.862

Gnomad SAS exome AF: 0.635

Gnomad FIN exome AF: 0.336

Gnomad NFE exome AF: 0.405

Gnomad OTH exome AF: 0.477

GnomAD4 exome AF: 0.433 AC: 632069 AN: 1459634 Hom.: 146005 Cov.: 36 AF XY: 0.439 AC XY: 318766 AN XY: 726150

Gnomad4 AFR exome AF: 0.485

Gnomad4 AMR exome AF: 0.586

Gnomad4 ASJ exome AF: 0.590

Gnomad4 EAS exome AF: 0.881

Gnomad4 SAS exome AF: 0.632

Gnomad4 FIN exome AF: 0.339

Gnomad4 NFE exome AF: 0.392

Gnomad4 OTH exome AF: 0.466

GnomAD4 genome AF: 0.456 AC: 69181 AN: 151820 Hom.: 16664 Cov.: 31 AF XY: 0.457 AC XY: 33914 AN XY: 74184

Gnomad4 AFR AF: 0.474

Gnomad4 AMR AF: 0.502

Gnomad4 ASJ AF: 0.596

Gnomad4 EAS AF: 0.860

Gnomad4 SAS AF: 0.646

Gnomad4 FIN AF: 0.329

Gnomad4 NFE AF: 0.399

Gnomad4 OTH AF: 0.526

Alfa AF: 0.434 Hom.: 11749

Bravo AF: 0.472

TwinsUK AF: 0.385 AC: 1426

ALSPAC AF: 0.382 AC: 1472

ESP6500AA AF: 0.464 AC: 2046

ESP6500EA AF: 0.412 AC: 3546

ExAC AF: 0.498 AC: 60432

Asia WGS AF: 0.742 AC: 2579 AN: 3478

EpiCase AF: 0.423

EpiControl AF: 0.424

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.017
DANN	Benign	0.84
DEOGEN2	Benign	0.031	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.042	T
MetaRNN	Benign	8.4e-7	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.18	N
MutationTaster	Benign	1.0	P;P
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.021
Sift	Benign	0.36	T
Sift4G	Benign	0.41	T
Polyphen		0.0	B
Vest4		0.028
MutPred		0.20		Loss of ubiquitination at K9 (P = 0.1322);
MPC		0.012
ClinPred		0.0076	T
GERP RS		-4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.24
gMVP		0.33

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

LitVar

Other links and lift over

dbSNP: rs12529; hg19: chr10-5136651; COSMIC: COSV65910253; COSMIC: COSV65910253;