Genetic Variant AKR1C3:c.85-2454A>G (chr10-5093956-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001253908.2(AKR1C3):c.85-2454A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.455 in 151,922 control chromosomes in the GnomAD database, including 16,664 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.46 ( 16663 hom., cov: 33)

Exomes 𝑓: 0.50 ( 1 hom. )

Consequence

AKR1C3
NM_001253908.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.32

Publications

13 publications found

Variant links:

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]

AKR1C3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.841 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKR1C3	NM_001253908.2 link	c.85-2454A>G		intron_variant	Intron 1 of 8		NP_001240837.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein
AKR1C3	ENST00000439082.7 link	c.85-2454A>G	intron_variant	Intron 1 of 8	5	ENSP00000401327.3
AKR1C3	ENST00000605149.5 link	c.16-2454A>G	intron_variant	Intron 1 of 8	2	ENSP00000474882.1
AKR1C3	ENST00000602997.5 link	c.16-2454A>G	intron_variant	Intron 2 of 5	3	ENSP00000474188.1

Frequencies

GnomAD3 genomes

AF:

0.455

AC:

69130

AN:

151796

Hom.:

16644

Cov.:

show subpopulations

Gnomad AFR

AF:

0.473

Gnomad AMI

AF:

0.475

Gnomad AMR

AF:

0.503

Gnomad ASJ

AF:

0.596

Gnomad EAS

AF:

0.861

Gnomad SAS

AF:

0.647

Gnomad FIN

AF:

0.329

Gnomad MID

AF:

0.640

Gnomad NFE

AF:

0.399

Gnomad OTH

AF:

0.520

GnomAD4 exome

AF:

0.500

AC:

AN:

Hom.:

Cov.:

AF XY:

0.500

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

1.00

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.250

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.455

AC:

69186

AN:

151916

Hom.:

16663

Cov.:

AF XY:

0.457

AC XY:

33937

AN XY:

74252

show subpopulations

African (AFR)

AF:

0.473

AC:

19591

AN:

41428

American (AMR)

AF:

0.503

AC:

7661

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.596

AC:

2067

AN:

3470

East Asian (EAS)

AF:

0.862

AC:

4443

AN:

5156

South Asian (SAS)

AF:

0.646

AC:

3118

AN:

4826

European-Finnish (FIN)

AF:

0.329

AC:

3472

AN:

10538

Middle Eastern (MID)

AF:

0.639

AC:

188

AN:

294

European-Non Finnish (NFE)

AF:

0.399

AC:

27108

AN:

67946

Other (OTH)

AF:

0.525

AC:

1106

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1835

3671

5506

7342

9177

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

636

1272

1908

2544

3180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.428

Hom.:

2454

Bravo

AF:

0.472

Asia WGS

AF:

0.744

AC:

2563

AN:

3448

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

1.4

(source)

DANN

Benign

0.43

PhyloP100

-1.3

PromoterAI

-0.0052

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over