Genetic Variant AKR1C4:p.Ser145Cys (chr10-5205821-C-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001818.5(AKR1C4):c.434C>G(p.Ser145Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 1,612,174 control chromosomes in the GnomAD database, including 17,158 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.11 ( 1186 hom., cov: 32)

Exomes 𝑓: 0.14 ( 15972 hom. )

Consequence

AKR1C4
NM_001818.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.112

Publications

36 publications found

Variant links:

Genes affected

AKR1C4 (HGNC:387): (aldo-keto reductase family 1 member C4) 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 bioreduction of chlordecone, a toxic organochlorine pesticide, to chlordecone alcohol in liver. This gene shares high sequence identity with three other gene members and is clustered with those three genes at chromosome 10p15-p14. [provided by RefSeq, Jul 2008]

AKR1C4 Gene-Disease associations (from GenCC):

46,XY disorder of sex development due to testicular 17,20-desmolase deficiency
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

AKR1C4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017965734).

BP6

Variant 10-5205821-C-G is Benign according to our data. Variant chr10-5205821-C-G is described in ClinVar as Benign. ClinVar VariationId is 2017865.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKR1C4	NM_001818.5 link	c.434C>G	p.Ser145Cys	missense_variant	Exon 4 of 9	ENST00000263126.3	NP_001809.4	P17516

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKR1C4	ENST00000263126.3 link	c.434C>G	p.Ser145Cys	missense_variant	Exon 4 of 9	1	NM_001818.5	ENSP00000263126.1		P17516
AKR1C4	ENST00000380448.5 link	c.434C>G	p.Ser145Cys	missense_variant	Exon 6 of 11	5		ENSP00000369814.1		P17516

Frequencies

GnomAD3 genomes

AF:

0.113

AC:

17182

AN:

152118

Hom.:

1183

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0383

Gnomad AMI

AF:

0.0932

Gnomad AMR

AF:

0.166

Gnomad ASJ

AF:

0.105

Gnomad EAS

AF:

0.101

Gnomad SAS

AF:

0.110

Gnomad FIN

AF:

0.123

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.147

Gnomad OTH

AF:

0.103

GnomAD2 exomes

AF:

0.138

AC:

34471

AN:

250398

AF XY:

0.136

show subpopulations

Gnomad AFR exome

AF:

0.0362

Gnomad AMR exome

AF:

0.202

Gnomad ASJ exome

AF:

0.102

Gnomad EAS exome

AF:

0.104

Gnomad FIN exome

AF:

0.126

Gnomad NFE exome

AF:

0.151

Gnomad OTH exome

AF:

0.142

GnomAD4 exome

AF:

0.144

AC:

210218

AN:

1459938

Hom.:

15972

Cov.:

AF XY:

0.142

AC XY:

103224

AN XY:

726324

show subpopulations

African (AFR)

AF:

0.0326

AC:

1090

AN:

33400

American (AMR)

AF:

0.203

AC:

9041

AN:

44632

Ashkenazi Jewish (ASJ)

AF:

0.0981

AC:

2557

AN:

26052

East Asian (EAS)

AF:

0.0898

AC:

3561

AN:

39642

South Asian (SAS)

AF:

0.108

AC:

9333

AN:

86116

European-Finnish (FIN)

AF:

0.134

AC:

7152

AN:

53360

Middle Eastern (MID)

AF:

0.0745

AC:

429

AN:

5758

European-Non Finnish (NFE)

AF:

0.152

AC:

169033

AN:

1110668

Other (OTH)

AF:

0.133

AC:

8022

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

7804

15608

23411

31215

39019

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6014

12028

18042

24056

30070

<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:

0.113

AC:

17198

AN:

152236

Hom.:

1186

Cov.:

AF XY:

0.113

AC XY:

8410

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0382

AC:

1588

AN:

41554

American (AMR)

AF:

0.167

AC:

2552

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.105

AC:

363

AN:

3466

East Asian (EAS)

AF:

0.102

AC:

526

AN:

5178

South Asian (SAS)

AF:

0.110

AC:

532

AN:

4826

European-Finnish (FIN)

AF:

0.123

AC:

1299

AN:

10602

Middle Eastern (MID)

AF:

0.0850

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.147

AC:

10014

AN:

68004

Other (OTH)

AF:

0.101

AC:

214

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

780

1561

2341

3122

3902

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

190

380

570

760

950

<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:

0.135

Hom.:

514

Bravo

AF:

0.114

TwinsUK

AF:

0.170

AC:

632

ALSPAC

AF:

0.165

AC:

634

ESP6500AA

AF:

0.0420

AC:

185

ESP6500EA

AF:

0.151

AC:

1302

ExAC

AF:

0.137

AC:

16590

Asia WGS

AF:

0.0940

AC:

325

AN:

3478

EpiCase

AF:

0.140

EpiControl

AF:

0.142

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.040

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.77

CADD

Benign

2.1

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.030

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0026

LIST_S2

Benign

0.61

.;T

MetaRNN

Benign

0.0018

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.050

N;N

PhyloP100

0.11

PrimateAI

Benign

0.44

PROVEAN

Benign

7.3

N;N

REVEL

Benign

0.055

Sift

Benign

1.0

T;T

Sift4G

Benign

0.78

T;T

Polyphen

0.0

B;B

Vest4

0.037

MPC

0.015

ClinPred

0.00030

GERP RS

3.2

Varity_R

0.13

gMVP

0.20

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over