rs119481075

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000197.2(HSD17B3):c.239G>A(p.Arg80Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,613,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R80W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

HSD17B3
NM_000197.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 2.78

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:

ENSG00000285269 (HGNC:):

ENSG00000285269 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-96254907-G-A is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.896

PP5

Variant 9-96254906-C-T is Pathogenic according to our data. Variant chr9-96254906-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 4874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-96254906-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B3	NM_000197.2 link	c.239G>A	p.Arg80Gln	missense_variant	Exon 3 of 11	ENST00000375263.8	NP_000188.1	P37058-1Q6FH62
SLC35D2-HSD17B3	NR_182427.1 link	n.3006G>A		non_coding_transcript_exon_variant	Exon 18 of 26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HSD17B3	ENST00000375263.8 link	c.239G>A	p.Arg80Gln	missense_variant	Exon 3 of 11	1	NM_000197.2	ENSP00000364412.3	P37058-1
ENSG00000285269	ENST00000643789.1 link	n.*1915G>A		non_coding_transcript_exon_variant	Exon 14 of 22			ENSP00000494818.1	A0A2R8Y5X9
ENSG00000285269	ENST00000643789.1 link	n.*1915G>A		3_prime_UTR_variant	Exon 14 of 22			ENSP00000494818.1	A0A2R8Y5X9

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000876

AC:

AN:

251144

Hom.:

AF XY:

0.0000737

AC XY:

AN XY:

135746

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000158

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000144

AC:

211

AN:

1461780

Hom.:

Cov.:

AF XY:

0.000132

AC XY:

AN XY:

727168

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000181

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000687

Hom.:

Bravo

AF:

0.000147

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Testosterone 17-beta-dehydrogenase deficiency

Pathogenic:4

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with pseudohermaphroditism, male, with gynecomastia (MIM#264300). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 22 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 8 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated short chain dehydrogenase domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least ten individuals with differences of sex development, both as homozygotes or compound heterozygotes; and consistently classified as pathogenic by diagnostic laboratories in ClinVar (PMIDs: 22445608, 27898418, 36606580). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

May 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 13, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 25, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Nov 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 80 of the HSD17B3 protein (p.Arg80Gln). This variant is present in population databases (rs119481075, gnomAD 0.01%). This missense change has been observed in individuals with 17-beta hydroxysteroid dehydrogenase 3 deficiency (PMID: 8626842, 17551466, 22445608, 23295294, 24025597). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4874). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt HSD17B3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects HSD17B3 function (PMID: 8075637, 12429500). For these reasons, this variant has been classified as Pathogenic. -

Mar 07, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a significant reduction in enzyme activity (Geissler et al., 1994); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25383892, 8075637, 23295294, 22857144, 22445608, 10599740, 27163392, 29566152, 33984517, 8626842, 31589614, 33144682, 33516834, 33586216) -

Pseudohermaphroditism

Pathogenic:1

Jul 13, 2007

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.39

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

D;.;.;T

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.94

D;D;D;D

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.90

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.9

H;H;.;.

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.7

D;D;.;.

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0030

D;D;.;.

Sift4G

Uncertain

0.0080

D;D;.;.

Polyphen

1.0

D;.;.;.

Vest4

0.85

MVP

0.97

MPC

0.52

ClinPred

0.93

GERP RS

4.8

Varity_R

0.88

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.31

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.31

Position offset: 37

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