rs119481077

Positions:

• chr9-96254907-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000197.2(HSD17B3):​c.238C>T​(p.Arg80Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,892 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R80Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: HSD17B3 NM_000197.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.43

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 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-96254906-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 4874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 9-96254907-G-A is Pathogenic according to our data. Variant chr9-96254907-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-96254907-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSD17B3	NM_000197.2	c.238C>T	p.Arg80Trp	missense_variant	3/11	ENST00000375263.8
SLC35D2-HSD17B3	NR_182427.1	n.3005C>T		non_coding_transcript_exon_variant	18/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSD17B3	ENST00000375263.8	c.238C>T	p.Arg80Trp	missense_variant	3/11	1	NM_000197.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152126 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000319 AC: 8 AN: 251118 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135720

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461766 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727168

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152126 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74304

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000850 Hom.: 0

Bravo AF: 0.0000113

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Testosterone 17-beta-dehydrogenase deficiency Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The HSD17B3 c.238C>T (p.Arg80Trp) variant has been reported in five studies and is found in a total of eight individuals with 17-beta-hydroxysteroid dehydrogenase III deficiency, including six who carried the variant in a homozygous state and two who carried the variant in a compound heterozygous state (Bilbao et al. 1998; Bertelloni et al. 2009; Omrani et al. 2011; George et al. 2011; Chuang et al. 2013). The variant has also been reported in a heterozygous state in at least eight unaffected family members and shown to segregate with disease in an autosomal recessive fashion (Bilbao et al. 1998; Omrani et al. 2011; George et al. 2011). The p.Arg80Trp variant was absent from 42 controls and is reported at a frequency of 0.00005 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Arg80Trp variant is classified as pathogenic for 17-beta-hydroxysteroid dehydrogenase III deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.80; 3Cnet: 0.92). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000004877 / PMID: 24025597 ) and a different missense change at the same codon (p.Arg80Gln; ClinVar ID: VCV000004874 ) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 04, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 80 of the HSD17B3 protein (p.Arg80Trp). This variant is present in population databases (rs119481077, gnomAD 0.006%). This missense change has been observed in individuals with male pseudohermaphroditism with gynecomastia (PMID: 9758445, 21214500, 22212252, 27899157). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4877). 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 with a positive predictive value of 80%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (PMID: 9758445). This variant disrupts the p.Arg80 amino acid residue in HSD17B3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8075637, 8626842, 12429500, 17551466). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Pseudohermaphroditism Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

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

Jun 02, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D;.;.;T
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.7	H;H;.;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-7.6	D;D;.;.
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;D;.;.
Sift4G	Pathogenic	0.0010	D;D;.;.
Polyphen		1.0	D;.;.;.
Vest4		0.90
MutPred		0.96		Gain of ubiquitination at K84 (P = 0.0546);Gain of ubiquitination at K84 (P = 0.0546);Gain of ubiquitination at K84 (P = 0.0546);Gain of ubiquitination at K84 (P = 0.0546);
MVP		0.99
MPC		0.71
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.95
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.24		Position offset: 36

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs119481077; hg19: chr9-99017189; COSMIC: COSV64558593; COSMIC: COSV64558593;