10-5102173-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003739.6(AKR1C3):c.643G>A(p.Ala215Thr) variant causes a missense change involving the alteration of a conserved nucleotide. 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 not provided (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: AKR1C3 NM_003739.6 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 7.96

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.753

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKR1C3	NM_003739.6	c.643G>A	p.Ala215Thr	missense_variant	6/9	ENST00000380554.5
AKR1C3	NM_001253908.2	c.643G>A	p.Ala215Thr	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKR1C3	ENST00000380554.5	c.643G>A	p.Ala215Thr	missense_variant	6/9	1	NM_003739.6	P4
AKR1C3	ENST00000439082.7	c.643G>A	p.Ala215Thr	missense_variant	6/9	5		A1
AKR1C3	ENST00000605149.5	c.574G>A	p.Ala192Thr	missense_variant	6/9	2
AKR1C3	ENST00000605781.5	n.822G>A		non_coding_transcript_exon_variant	6/6	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Hypotension Other:1

not provided, no classification provided

literature only

Centre for molecular medicine, Karolinska Institutet

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.038
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.0044	T
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Benign	-0.59	T
MutationTaster	Benign	0.89	D;D
PrimateAI	Uncertain	0.50	T
REVEL	Benign	0.19
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		0.92	.;.;P
Vest4		0.46
MutPred		0.83		Loss of catalytic residue at A215 (P = 0.003);.;Loss of catalytic residue at A215 (P = 0.003);
MVP		0.37
MPC		0.077
ClinPred		0.97	D
GERP RS		2.1
Varity_R		0.80
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs483352820; hg19: chr10-5144365;