10-5102485-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

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

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 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	c.681G>T	p.Trp227Cys	missense_variant, splice_region_variant	7/9	ENST00000380554.5
AKR1C3	NM_001253908.2	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	c.681G>T	p.Trp227Cys	missense_variant, splice_region_variant	7/9	1	NM_003739.6	P4
AKR1C3	ENST00000439082.7	c.681G>T	p.Trp227Cys	missense_variant, splice_region_variant	7/9	5		A1
AKR1C3	ENST00000605149.5	c.612G>T	p.Trp204Cys	missense_variant, splice_region_variant	7/9	2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1 AN: 151480 Hom.: 0 Cov.: 28 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.: 32

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000660 AC: 1 AN: 151480 Hom.: 0 Cov.: 28 AF XY: 0.0000135 AC XY: 1 AN XY: 73920

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

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	T
BayesDel_noAF	Benign	-0.39
Cadd	Uncertain	24
Dann	Benign	0.97
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.0081	T
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.51	T
REVEL	Benign	0.18
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	D
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

Other links and lift over

dbSNP: rs1554786231; hg19: chr10-5144677;