10-5096522-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003739.6(AKR1C3):c.197G>A(p.Arg66Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00437 in 1,613,744 control chromosomes in the GnomAD database, including 249 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.023 (143 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (106 hom.)
• Consequence: AKR1C3 NM_003739.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.312

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028518438).
• BP6: Variant 10-5096522-G-A is Benign according to our data. Variant chr10-5096522-G-A is described in ClinVar as [Benign]. Clinvar id is 783568.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0777 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKR1C3	NM_003739.6	c.197G>A	p.Arg66Gln	missense_variant	2/9	ENST00000380554.5
AKR1C3	NM_001253908.2	c.197G>A	p.Arg66Gln	missense_variant	2/9
AKR1C3	NM_001253909.2	c.197G>A	p.Arg66Gln	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKR1C3	ENST00000380554.5	c.197G>A	p.Arg66Gln	missense_variant	2/9	1	NM_003739.6	P4

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 3481 AN: 152046 Hom.: 140 Cov.: 32

Gnomad AFR AF: 0.0796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00826

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.00589 AC: 1479 AN: 251288 Hom.: 48 AF XY: 0.00435 AC XY: 591 AN XY: 135804

Gnomad AFR exome AF: 0.0769

Gnomad AMR exome AF: 0.00477

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00242 AC: 3542 AN: 1461580 Hom.: 106 Cov.: 32 AF XY: 0.00214 AC XY: 1557 AN XY: 727094

Gnomad4 AFR exome AF: 0.0811

Gnomad4 AMR exome AF: 0.00496

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000233

Gnomad4 OTH exome AF: 0.00520

GnomAD4 genome AF: 0.0230 AC: 3504 AN: 152164 Hom.: 143 Cov.: 32 AF XY: 0.0223 AC XY: 1657 AN XY: 74414

Gnomad4 AFR AF: 0.0799

Gnomad4 AMR AF: 0.00825

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00243 Hom.: 5

Bravo AF: 0.0254

ESP6500AA AF: 0.0724 AC: 319

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00689 AC: 837

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	9.4
Dann	Benign	0.85
DEOGEN2	Benign	0.037	T;.;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.68	T;T;T;T
MetaRNN	Benign	0.0029	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.21	T
Sift4G	Benign	0.47	T;T;T;T
Polyphen		0.69	.;.;.;P
Vest4		0.18, 0.071, 0.18
MVP		0.24
MPC		0.013
ClinPred		0.0043	T
GERP RS		-1.8
Varity_R		0.23
gMVP		0.26

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: rs35961894; hg19: chr10-5138714; COSMIC: COSV65910697; COSMIC: COSV65910697;