10-5097450-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.269A>G(p.His90Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000293 in 1,613,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: AKR1C3 NM_003739.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.73

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=0.02999872).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKR1C3	NM_003739.6	c.269A>G	p.His90Arg	missense_variant	3/9	ENST00000380554.5
AKR1C3	NM_001253908.2	c.269A>G	p.His90Arg	missense_variant	3/9
AKR1C3	NM_001253909.2	c.269A>G	p.His90Arg	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKR1C3	ENST00000380554.5	c.269A>G	p.His90Arg	missense_variant	3/9	1	NM_003739.6	P4

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152118 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000346 AC: 87 AN: 251124 Hom.: 0 AF XY: 0.000258 AC XY: 35 AN XY: 135738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000317

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000296 AC: 433 AN: 1461438 Hom.: 0 Cov.: 29 AF XY: 0.000285 AC XY: 207 AN XY: 727026

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00218

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.000276

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152236 Hom.: 0 Cov.: 31 AF XY: 0.000322 AC XY: 24 AN XY: 74446

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000339 Hom.: 0

Bravo AF: 0.000298

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000264 AC: 32

EpiCase AF: 0.000327

EpiControl AF: 0.000178

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

Mar 11, 2022

The c.269A>G (p.H90R) alteration is located in exon 3 (coding exon 3) of the AKR1C3 gene. This alteration results from a A to G substitution at nucleotide position 269, causing the histidine (H) at amino acid position 90 to be replaced by an arginine (R). 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	0.61
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	6.3
Dann	Benign	0.96
DEOGEN2	Benign	0.038	T;.;T;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.55	T;T;T;T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.030	T;T;T;T
MetaSVM	Benign	-0.77	T
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.40	T
Sift4G	Uncertain	0.016	D;D;D;D
Polyphen		0.99	.;.;.;D
Vest4		0.20, 0.19, 0.21
MVP		0.62
MPC		0.081
ClinPred		0.13	T
GERP RS		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.54
gMVP		0.61

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: rs200981816; hg19: chr10-5139642;