9-96235528-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000197.2(HSD17B3):c.865G>A(p.Gly289Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0618 in 1,613,652 control chromosomes in the GnomAD database, including 4,380 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.077 ( 652 hom., cov: 33)

Exomes 𝑓: 0.060 ( 3728 hom. )

Consequence

HSD17B3
NM_000197.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.410

Publications

47 publications found

Variant links:

Genes affected

HSD17B3 (HGNC:5212): (hydroxysteroid 17-beta dehydrogenase 3) This isoform of 17 beta-hydroxysteroid dehydrogenase is expressed predominantly in the testis and catalyzes the conversion of androstenedione to testosterone. It preferentially uses NADP as cofactor. Deficiency can result in male pseudohermaphroditism with gynecomastia. [provided by RefSeq, Jul 2008]

HSD17B3 Gene-Disease associations (from GenCC):

46,XY disorder of sex development due to 17-beta-hydroxysteroid dehydrogenase 3 deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

HSD17B3 links:

ENSG00000285269 (HGNC:):

ENSG00000285269 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002269566).

BP6

Variant 9-96235528-C-T is Benign according to our data. Variant chr9-96235528-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 255511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.228 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B3	NM_000197.2 link	c.865G>A	p.Gly289Ser	missense_variant	Exon 11 of 11	ENST00000375263.8	NP_000188.1	P37058-1Q6FH62
SLC35D2-HSD17B3	NR_182427.1 link	n.3632G>A		non_coding_transcript_exon_variant	Exon 26 of 26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HSD17B3	ENST00000375263.8 link	c.865G>A	p.Gly289Ser	missense_variant	Exon 11 of 11	1	NM_000197.2	ENSP00000364412.3	P37058-1
ENSG00000285269	ENST00000643789.1 link	n.*2541G>A		non_coding_transcript_exon_variant	Exon 22 of 22			ENSP00000494818.1	A0A2R8Y5X9
ENSG00000285269	ENST00000643789.1 link	n.*2541G>A		3_prime_UTR_variant	Exon 22 of 22			ENSP00000494818.1	A0A2R8Y5X9

Frequencies

GnomAD3 genomes

AF:

0.0775

AC:

11786

AN:

152124

Hom.:

653

Cov.:

show subpopulations

Gnomad AFR

AF:

0.113

Gnomad AMI

AF:

0.0833

Gnomad AMR

AF:

0.0584

Gnomad ASJ

AF:

0.123

Gnomad EAS

AF:

0.239

Gnomad SAS

AF:

0.0771

Gnomad FIN

AF:

0.0464

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.0498

Gnomad OTH

AF:

0.0847

GnomAD2 exomes

AF:

0.0724

AC:

18153

AN:

250766

AF XY:

0.0712

show subpopulations

Gnomad AFR exome

AF:

0.110

Gnomad AMR exome

AF:

0.0489

Gnomad ASJ exome

AF:

0.124

Gnomad EAS exome

AF:

0.228

Gnomad FIN exome

AF:

0.0417

Gnomad NFE exome

AF:

0.0495

Gnomad OTH exome

AF:

0.0659

GnomAD4 exome

AF:

0.0602

AC:

87913

AN:

1461410

Hom.:

3728

Cov.:

AF XY:

0.0607

AC XY:

44142

AN XY:

726984

show subpopulations

African (AFR)

AF:

0.113

AC:

3774

AN:

33474

American (AMR)

AF:

0.0493

AC:

2202

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.128

AC:

3352

AN:

26128

East Asian (EAS)

AF:

0.239

AC:

9493

AN:

39676

South Asian (SAS)

AF:

0.0747

AC:

6438

AN:

86198

European-Finnish (FIN)

AF:

0.0416

AC:

2219

AN:

53368

Middle Eastern (MID)

AF:

0.0529

AC:

305

AN:

5766

European-Non Finnish (NFE)

AF:

0.0500

AC:

55571

AN:

1111722

Other (OTH)

AF:

0.0755

AC:

4559

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

4348

8696

13043

17391

21739

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0774

AC:

11788

AN:

152242

Hom.:

652

Cov.:

AF XY:

0.0778

AC XY:

5794

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.113

AC:

4699

AN:

41536

American (AMR)

AF:

0.0581

AC:

889

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.123

AC:

427

AN:

3472

East Asian (EAS)

AF:

0.239

AC:

1237

AN:

5180

South Asian (SAS)

AF:

0.0769

AC:

371

AN:

4824

European-Finnish (FIN)

AF:

0.0464

AC:

492

AN:

10596

Middle Eastern (MID)

AF:

0.119

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0498

AC:

3386

AN:

68020

Other (OTH)

AF:

0.0833

AC:

176

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

541

1082

1624

2165

2706

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0644

Hom.:

1377

Bravo

AF:

0.0815

TwinsUK

AF:

0.0491

AC:

182

ALSPAC

AF:

0.0615

AC:

237

ESP6500AA

AF:

0.104

AC:

459

ESP6500EA

AF:

0.0517

AC:

445

ExAC

AF:

0.0720

AC:

8736

Asia WGS

AF:

0.146

AC:

512

AN:

3478

EpiCase

AF:

0.0546

EpiControl

AF:

0.0591

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 04, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29998616, 28859874, 19214745, 9709959, 25605705, 12210481, 23139742, 20059664, 23295294) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Testosterone 17-beta-dehydrogenase deficiency

Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.55

CADD

Benign

1.4

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.070

T;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.00093

LIST_S2

Benign

0.30

T;T

MetaRNN

Benign

0.0023

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.9

N;.

PhyloP100

-0.41

PrimateAI

Benign

0.25

PROVEAN

Benign

1.1

N;N

REVEL

Benign

0.15

Sift

Benign

0.81

T;T

Sift4G

Benign

0.81

T;T

Polyphen

0.0060

B;.

Vest4

0.10

MPC

0.16

ClinPred

0.0038

GERP RS

-5.2

Varity_R

0.024

gMVP

0.47

Mutation Taster

=99/1

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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9-96235528-C-T

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