rs142236065

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_000197.2(HSD17B3):c.599C>T(p.Ala200Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000397 in 1,611,610 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A200A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

HSD17B3
NM_000197.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: 6.09

Publications

4 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: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.866

PP5

Variant 9-96245352-G-A is Pathogenic according to our data. Variant chr9-96245352-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 435472.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B3	NM_000197.2 link	c.599C>T	p.Ala200Val	missense_variant	Exon 8 of 11	ENST00000375263.8	NP_000188.1
SLC35D2-HSD17B3	NR_182427.1 link	n.3366C>T		non_coding_transcript_exon_variant	Exon 23 of 26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
HSD17B3	ENST00000375263.8 link	c.599C>T	p.Ala200Val	missense_variant	Exon 8 of 11	1	NM_000197.2	ENSP00000364412.3
ENSG00000285269	ENST00000643789.1 link	n.*2275C>T		non_coding_transcript_exon_variant	Exon 19 of 22			ENSP00000494818.1
ENSG00000285269	ENST00000643789.1 link	n.*2275C>T		3_prime_UTR_variant	Exon 19 of 22			ENSP00000494818.1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251332

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000404

AC:

AN:

1459354

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

726194

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33438

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86218

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000505

AC:

AN:

1109716

Other (OTH)

AF:

0.0000166

AC:

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.437

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000328

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68052

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.415

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000472

Hom.:

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Testosterone 17-beta-dehydrogenase deficiency

Pathogenic:3

Nov 20, 2023

Clinical Biochemistry Laboratory, Health Services Laboratory

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG:PM1 PM2 PP2 PP3 PP5

Sep 02, 2016

Genetic Services Laboratory, University of Chicago

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 10, 2024

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: HSD17B3 c.599C>T (p.Ala200Val) results in a non-conservative amino acid change located in the NAD(P)-binding Rossmann-fold domain (IPR036291) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251332 control chromosomes. c.599C>T has been reported in the literature in individuals with clinical features of Testosterone 17-beta-dehydrogenase deficiency, including at least one compound heterozygote (e.g. Phelan_2015, Labcorp (formerly Invitae)). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal enzyme activity in vitro (e.g. Yazawa_2020). The following publications have been ascertained in the context of this evaluation (PMID: 25740850, 31614207). ClinVar contains an entry for this variant (Variation ID: 435472). Based on the evidence outlined above, the variant was classified as likely pathogenic.

not provided

Pathogenic:1Uncertain:1

Oct 26, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 200 of the HSD17B3 protein (p.Ala200Val). This variant is present in population databases (rs142236065, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of 17-beta hydroxysteroid dehydrogenase 3 deficiency (PMID: 25740850; Invitae). ClinVar contains an entry for this variant (Variation ID: 435472). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HSD17B3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

May 20, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a deleterious effect on enzymatic function (PMID: 31614207); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 36606580, Yazawa2021 [abstract], 25740850, 31614207)

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.68

D;.;.

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.87

D;D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Uncertain

2.9

M;M;.

PhyloP100

6.1

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.6

D;D;.

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0020

D;D;.

Sift4G

Uncertain

0.0050

D;D;.

Vest4

0.91

ClinPred

0.94

GERP RS

5.0

Varity_R

0.68

gMVP

0.93

Mutation Taster

=8/92

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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