Variant rs119481078 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

The NM_000197.2(HSD17B3):c.166G>A(p.Ala56Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,340 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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

HSD17B3
NM_000197.2 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 3.93

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 10 ACMG points.

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, 0.983

PP5

Variant 9-96298451-C-T is Pathogenic according to our data. Variant chr9-96298451-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4879.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSD17B3	NM_000197.2 linkuse as main transcript	c.166G>A	p.Ala56Thr	missense_variant	2/11	ENST00000375263.8	NP_000188.1	P37058-1Q6FH62
SLC35D2-HSD17B3	NR_182427.1 linkuse as main transcript	n.2933G>A		non_coding_transcript_exon_variant	17/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HSD17B3	ENST00000375263.8 linkuse as main transcript	c.166G>A	p.Ala56Thr	missense_variant	2/11	1	NM_000197.2	ENSP00000364412.3	P37058-1
ENSG00000285269	ENST00000643789.1 linkuse as main transcript	n.*1842G>A		non_coding_transcript_exon_variant	13/22			ENSP00000494818.1	A0A2R8Y5X9
ENSG00000285269	ENST00000643789.1 linkuse as main transcript	n.*1842G>A		3_prime_UTR_variant	13/22			ENSP00000494818.1	A0A2R8Y5X9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251394

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461340

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727044

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:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Testosterone 17-beta-dehydrogenase deficiency

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1998	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Biochemistry Laboratory, Health Services Laboratory	Nov 20, 2023	ACMG:PM1 PM2 PP1 PP2 PP3 PP4 PP5 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.77

D;.;.;T

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

M;M;.;.

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.0

D;D;.;.

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0030

D;D;.;.

Sift4G

Uncertain

0.0070

D;D;.;.

Polyphen

1.0

D;.;.;.

Vest4

0.92

MutPred

0.95

Gain of phosphorylation at A56 (P = 0.082);Gain of phosphorylation at A56 (P = 0.082);Gain of phosphorylation at A56 (P = 0.082);Gain of phosphorylation at A56 (P = 0.082);

MVP

0.99

MPC

0.68

ClinPred

0.96

GERP RS

4.8

Varity_R

0.70

gMVP

0.92

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