chr9-96235528-C-T

Position:

chr9-96235528-C-T

Variant summary

Our verdict is Benign. Variant got -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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G289C) has been classified 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

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 links:

SLC35D2-HSD17B3 (HGNC:):

SLC35D2-HSD17B3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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. Variant chr9-96235528-C-T is described in Lovd as [Benign].

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/exons	MANE	UniProt
HSD17B3	NM_000197.2 linkuse as main transcript	c.865G>A	p.Gly289Ser	missense_variant	11/11	ENST00000375263.8
SLC35D2-HSD17B3	NR_182427.1 linkuse as main transcript	n.3632G>A		non_coding_transcript_exon_variant	26/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSD17B3	ENST00000375263.8 linkuse as main transcript	c.865G>A	p.Gly289Ser	missense_variant	11/11	1	NM_000197.2	P1	P37058-1

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

GnomAD3 exomes

AF:

0.0724

AC:

18153

AN:

250766

Hom.:

1034

AF XY:

0.0712

AC XY:

9653

AN XY:

135524

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 SAS exome

AF:

0.0767

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

Gnomad4 AFR exome

AF:

0.113

Gnomad4 AMR exome

AF:

0.0493

Gnomad4 ASJ exome

AF:

0.128

Gnomad4 EAS exome

AF:

0.239

Gnomad4 SAS exome

AF:

0.0747

Gnomad4 FIN exome

AF:

0.0416

Gnomad4 NFE exome

AF:

0.0500

Gnomad4 OTH exome

AF:

0.0755

GnomAD4 genome

AF:

0.0774

AC:

11788

AN:

152242

Hom.:

652

Cov.:

AF XY:

0.0778

AC XY:

5794

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.113

Gnomad4 AMR

AF:

0.0581

Gnomad4 ASJ

AF:

0.123

Gnomad4 EAS

AF:

0.239

Gnomad4 SAS

AF:

0.0769

Gnomad4 FIN

AF:

0.0464

Gnomad4 NFE

AF:

0.0498

Gnomad4 OTH

AF:

0.0833

Alfa

AF:

0.0649

Hom.:

682

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

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2019	This variant is associated with the following publications: (PMID: 29998616, 28859874, 19214745, 9709959, 25605705, 12210481, 23139742, 20059664, 23295294) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Testosterone 17-beta-dehydrogenase deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

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

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;.

MutationTaster

Benign

1.0

P;P

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over