Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate

The NM_000197.2(HSD17B3):c.803G>A(p.Cys268Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. C268C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

HSD17B3
NM_000197.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 2.83

Publications

6 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.877

PP5

Variant 9-96240777-C-T is Pathogenic according to our data. Variant chr9-96240777-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 4881.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000197.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B3	NM_000197.2	MANE Select	c.803G>A	p.Cys268Tyr	missense	Exon 10 of 11	NP_000188.1
	SLC35D2-HSD17B3	NR_182427.1		n.3570G>A		non_coding_transcript_exon	Exon 25 of 26

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HSD17B3	ENST00000375263.8	TSL:1 MANE Select	c.803G>A	p.Cys268Tyr	missense	Exon 10 of 11	ENSP00000364412.3
ENSG00000285269	ENST00000643789.1		n.*2479G>A		non_coding_transcript_exon	Exon 21 of 22	ENSP00000494818.1
ENSG00000285269	ENST00000643789.1		n.*2479G>A		3_prime_UTR	Exon 21 of 22	ENSP00000494818.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Testosterone 17-beta-dehydrogenase deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.15

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.68

M_CAP

Uncertain

0.085

MetaRNN

Pathogenic

0.88

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

1.7

PhyloP100

2.8

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-3.4

REVEL

Pathogenic

0.74

Sift

Benign

0.13

Sift4G

Benign

0.28

Polyphen

1.0

Vest4

0.77

MutPred

0.82

Loss of catalytic residue at L269 (P = 0.0439)

MVP

0.86

MPC

0.72

ClinPred

0.96

GERP RS

4.3

Varity_R

0.39

gMVP

0.78

Mutation Taster

=34/66

disease causing (ClinVar)

(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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rs119481080

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over