rs119481076

chr9-96244393-G-Achr9-96244393-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000197.2(HSD17B3):c.608C>T(p.Ala203Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000013 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A203A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: HSD17B3 NM_000197.2 missense, splice_region
• Scores: Splicing: ADA: 0.01508
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.71

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]

SLC35D2-HSD17B3 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 9-96244393-G-A is Pathogenic according to our data. Variant chr9-96244393-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSD17B3	NM_000197.2	c.608C>T	p.Ala203Val	missense_variant, splice_region_variant	9/11	ENST00000375263.8
SLC35D2-HSD17B3	NR_182427.1	n.3375C>T		splice_region_variant, non_coding_transcript_exon_variant	24/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSD17B3	ENST00000375263.8	c.608C>T	p.Ala203Val	missense_variant, splice_region_variant	9/11	1	NM_000197.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251466 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135906

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461842 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727228

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000192 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 13, 2023	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 203 of the HSD17B3 protein (p.Ala203Val). This variant is present in population databases (rs119481076, gnomAD 0.009%). This missense change has been observed in individuals with 17-beta-hydroxysteroid dehydrogenase type 3 deficiency (PMID: 8075637, 23295294, 25740850, 27163392). ClinVar contains an entry for this variant (Variation ID: 4875). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects HSD17B3 function (PMID: 8075637). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 30, 2023	Published functional studies demonstrate loss of enzymatic activity (Geissler et al., 1994); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23295294, 25525159, 8075637, 8550739, 25536660, 18296911, 31589614, 25740850, 36077423, 27163392) -

Testosterone 17-beta-dehydrogenase deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1994

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 2016

- -

Pseudohermaphroditism Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

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

Jan 23, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;.;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.84	T;D;D
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	3.1	M;M;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.6	N;N;.
REVEL	Pathogenic	0.67
Sift	Benign	0.31	T;T;.
Sift4G	Benign	0.54	T;T;.
Polyphen		0.71	P;.;.
Vest4		0.59
MutPred		0.94		Gain of methylation at K202 (P = 0.0678);Gain of methylation at K202 (P = 0.0678);.;
MVP		0.94
MPC		0.23
ClinPred		0.62	D
GERP RS		4.8
Varity_R		0.27
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.015
dbscSNV1_RF	Benign	0.15
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

Other links and lift over

dbSNP: rs119481076; hg19: chr9-99006675; COSMIC: COSV100931226; COSMIC: COSV100931226;