10-5102622-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003739.6(AKR1C3):c.818A>G(p.Asn273Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,497,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: AKR1C3 NM_003739.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0750

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.017239153).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKR1C3	NM_003739.6	c.818A>G	p.Asn273Ser	missense_variant	7/9	ENST00000380554.5
AKR1C3	NM_001253908.2	c.818A>G	p.Asn273Ser	missense_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKR1C3	ENST00000380554.5	c.818A>G	p.Asn273Ser	missense_variant	7/9	1	NM_003739.6	P4
AKR1C3	ENST00000439082.7	c.818A>G	p.Asn273Ser	missense_variant	7/9	5		A1
AKR1C3	ENST00000605149.5	c.749A>G	p.Asn250Ser	missense_variant	7/9	2

Frequencies

GnomAD3 genomes AF: 0.0000989 AC: 15 AN: 151640 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.000629

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000120 AC: 15 AN: 124992 Hom.: 0 AF XY: 0.0000934 AC XY: 6 AN XY: 64214

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000601

Gnomad SAS exome AF: 0.000162

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000912

Gnomad OTH exome AF: 0.000319

GnomAD4 exome AF: 0.000122 AC: 164 AN: 1345306 Hom.: 0 Cov.: 33 AF XY: 0.000120 AC XY: 79 AN XY: 656706

Gnomad4 AFR exome AF: 0.000167

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000299

Gnomad4 SAS exome AF: 0.000320

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000106

Gnomad4 OTH exome AF: 0.000253

GnomAD4 genome AF: 0.0000988 AC: 15 AN: 151758 Hom.: 0 Cov.: 28 AF XY: 0.000121 AC XY: 9 AN XY: 74160

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.000629

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000642

ESP6500AA AF: 0.000229 AC: 1

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.000103 AC: 12

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 28, 2023

The c.818A>G (p.N273S) alteration is located in exon 7 (coding exon 7) of the AKR1C3 gene. This alteration results from a A to G substitution at nucleotide position 818, causing the asparagine (N) at amino acid position 273 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	Benign	0.078
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	5.1
Dann	Benign	0.89
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.68	T;T;T
M_CAP	Benign	0.00089	T
MetaRNN	Benign	0.017	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.43	T
REVEL	Benign	0.016
Sift4G	Benign	0.29	T;T;T
Polyphen		0.0040	.;.;B
Vest4		0.22
MVP		0.27
MPC		0.012
ClinPred		0.0072	T
GERP RS		0.79
Varity_R		0.18
gMVP		0.31

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: rs368182129; hg19: chr10-5144814;