NM_000197.2:c.194C>T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1_ModeratePM1PM2PP3_StrongPP5_Very_Strong

The NM_000197.2(HSD17B3):c.194C>T(p.Ser65Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,054 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 Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Synonymous variant affecting the same amino acid position (i.e. S65S) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

HSD17B3
NM_000197.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 3.42

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 18 ACMG points.

PS1

Transcript NM_000197.2 (HSD17B3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM1

In a binding_site (size 29) in uniprot entity DHB3_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000197.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.974

PP5

Variant 9-96298423-G-A is Pathogenic according to our data. Variant chr9-96298423-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 242504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-96298423-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B3	NM_000197.2 link	c.194C>T	p.Ser65Leu	missense_variant	Exon 2 of 11	ENST00000375263.8	NP_000188.1	P37058-1Q6FH62
SLC35D2-HSD17B3	NR_182427.1 link	n.2961C>T		non_coding_transcript_exon_variant	Exon 17 of 26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HSD17B3	ENST00000375263.8 link	c.194C>T	p.Ser65Leu	missense_variant	Exon 2 of 11	1	NM_000197.2	ENSP00000364412.3	P37058-1
ENSG00000285269	ENST00000643789.1 link	n.*1870C>T		non_coding_transcript_exon_variant	Exon 13 of 22			ENSP00000494818.1	A0A2R8Y5X9
ENSG00000285269	ENST00000643789.1 link	n.*1870C>T		3_prime_UTR_variant	Exon 13 of 22			ENSP00000494818.1	A0A2R8Y5X9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251432

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461054

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

726914

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Testosterone 17-beta-dehydrogenase deficiency

Pathogenic:2

Dec 05, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HSD17B3 c.194C>T (p.Ser65Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251432 control chromosomes (gnomAD). c.194C>T has been reported in the literature in multiple individuals affected with Testosterone 17-beta-dehydrogenase deficiency (e.g. Andersson_1996, Baxter_2015, Hughes_2019, Zhu_2022). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant inactivated enzyme activity almost completely (Andersson_1996). The following publications have been ascertained in the context of this evaluation (PMID: 8550739, 25383892, 30668521, 36154887). ClinVar contains an entry for this variant (Variation ID: 242504). Based on the evidence outlined above, the variant was classified as pathogenic. -

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.194C>T p.Ser65Leu variant in HSD17B3 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Ser65Leu variant has allele frequency 0.001% in gnomAD Exomes and is novel not in any individuals in 1000 Genomes. This variant has not been reported to the ClinVar database. The amino acid change p.Ser65Leu in HSD17B3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 65 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance VUS. -

not provided

Pathogenic:1

Nov 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 65 of the HSD17B3 protein (p.Ser65Leu). This variant is present in population databases (rs747329682, gnomAD no frequency). This missense change has been observed in individuals with clinical features of 17-beta-hydroxysteroid dehydrogenase type 3 deficiency (PMID: 8550739, 25326637, 30668521, 32449406, 36154887, 37741351). ClinVar contains an entry for this variant (Variation ID: 242504). 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 not expected to disrupt HSD17B3 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects HSD17B3 function (PMID: 8550739, 37741351). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

D;.;.;T

Eigen

Benign

-0.10

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.47

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Benign

0.080

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Uncertain

-0.058

MutationAssessor

Benign

1.8

L;L;.;.

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.1

D;D;.;.

REVEL

Uncertain

0.56

Sift

Uncertain

0.0020

D;D;.;.

Sift4G

Uncertain

0.0030

D;D;.;.

Polyphen

0.68

P;.;.;.

Vest4

0.75

MutPred

0.93

Loss of disorder (P = 0.0768);Loss of disorder (P = 0.0768);Loss of disorder (P = 0.0768);Loss of disorder (P = 0.0768);

MVP

0.91

MPC

0.40

ClinPred

0.97

GERP RS

4.8

Varity_R

0.56

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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