10-5102630-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_003739.6(AKR1C3):c.826C>T(p.Arg276Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000637 in 1,483,840 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00067 (3 hom.)
• Consequence: AKR1C3 NM_003739.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.381

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_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15485898).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKR1C3	NM_003739.6	c.826C>T	p.Arg276Cys	missense_variant	7/9	ENST00000380554.5
AKR1C3	NM_001253908.2	c.826C>T	p.Arg276Cys	missense_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKR1C3	ENST00000380554.5	c.826C>T	p.Arg276Cys	missense_variant	7/9	1	NM_003739.6	P4
AKR1C3	ENST00000439082.7	c.826C>T	p.Arg276Cys	missense_variant	7/9	5		A1
AKR1C3	ENST00000605149.5	c.757C>T	p.Arg253Cys	missense_variant	7/9	2

Frequencies

GnomAD3 genomes AF: 0.000356 AC: 54 AN: 151696 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000970

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000919

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: 0.000515

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000400 AC: 44 AN: 110038 Hom.: 0 AF XY: 0.000414 AC XY: 23 AN XY: 55606

Gnomad AFR exome AF: 0.000113

Gnomad AMR exome AF: 0.000688

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000299

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000622

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000669 AC: 891 AN: 1332028 Hom.: 3 Cov.: 33 AF XY: 0.000680 AC XY: 441 AN XY: 648800

Gnomad4 AFR exome AF: 0.000136

Gnomad4 AMR exome AF: 0.000592

Gnomad4 ASJ exome AF: 0.0000511

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000240

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000788

Gnomad4 OTH exome AF: 0.000529

GnomAD4 genome AF: 0.000356 AC: 54 AN: 151812 Hom.: 0 Cov.: 29 AF XY: 0.000364 AC XY: 27 AN XY: 74178

Gnomad4 AFR AF: 0.0000967

Gnomad4 AMR AF: 0.000918

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000125 Hom.: 0

Bravo AF: 0.000393

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000236 AC: 2

ExAC AF: 0.000166 AC: 19

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

Aug 23, 2021

The c.826C>T (p.R276C) alteration is located in exon 7 (coding exon 7) of the AKR1C3 gene. This alteration results from a C to T substitution at nucleotide position 826, causing the arginine (R) at amino acid position 276 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	Uncertain	0.43
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	18
Dann	Uncertain	0.99
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.029	N
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	0.99	N;N
PrimateAI	Uncertain	0.57	T
REVEL	Benign	0.13
Sift4G	Uncertain	0.019	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.48
MVP		0.54
MPC		0.081
ClinPred		0.25	T
GERP RS		-4.1
Varity_R		0.53
gMVP		0.66

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: rs140613308; hg19: chr10-5144822; COSMIC: COSV99078054; COSMIC: COSV99078054;