rs201115371

Variant names:

• chr9-96254864-T-A
• rs201115371
• NM_000197.2:c.277+4A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 9P and 1B. PP3 PP5_Very_Strong BS1_Supporting

The NM_000197.2(HSD17B3):​c.277+4A>T variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000612 in 1,613,158 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00064 (1 hom.)
• Consequence: HSD17B3 NM_000197.2 splice_region, intron
• Scores: Splicing: ADA: 0.9985
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 4.29
• Publications: 15 publications found

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]

ENSG00000285269 (HGNC:):

HSD17B3-AS1 (HGNC:53136): (HSD17B3 antisense RNA 1)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 9-96254864-T-A is Pathogenic according to our data. Variant chr9-96254864-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 208587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000639 (934/1460978) while in subpopulation NFE AF = 0.000816 (907/1111292). AF 95% confidence interval is 0.000772. There are 1 homozygotes in GnomAdExome4. There are 482 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B3	NM_000197.2	c.277+4A>T		splice_region_variant, intron_variant	Intron 3 of 10	ENST00000375263.8	NP_000188.1
SLC35D2-HSD17B3	NR_182427.1	n.3044+4A>T		splice_region_variant, intron_variant	Intron 18 of 25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD17B3	ENST00000375263.8	c.277+4A>T		splice_region_variant, intron_variant	Intron 3 of 10	1	NM_000197.2	ENSP00000364412.3
ENSG00000285269	ENST00000643789.1	n.*1953+4A>T		splice_region_variant, intron_variant	Intron 14 of 21			ENSP00000494818.1

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152180 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000750

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000343 AC: 86 AN: 250920 AF XY: 0.000332

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.000713

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000639 AC: 934 AN: 1460978 Hom.: 1 Cov.: 31 AF XY: 0.000663 AC XY: 482 AN XY: 726814

African (AFR) AF: 0.0000598 AC: 2 AN: 33472

American (AMR) AF: 0.0000447 AC: 2 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86176

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53410

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.000816 AC: 907 AN: 1111292

Other (OTH) AF: 0.000348 AC: 21 AN: 60368

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152180 Hom.: 0 Cov.: 31 AF XY: 0.000377 AC XY: 28 AN XY: 74354

African (AFR) AF: 0.0000483 AC: 2 AN: 41438

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000750 AC: 51 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000669 Hom.: 0

Bravo AF: 0.000397

EpiCase AF: 0.000491

EpiControl AF: 0.000415

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Testosterone 17-beta-dehydrogenase deficiency Pathogenic:6

Jan 25, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 27, 2025

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PVS1 very strong, PM3 very strong -

Dec 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.277+4A>T variant in HSD17B3 has been reported in 12 patients with male pse udohermaphroditism (4 homozygotes and 8 compound heterozygotes) and segregated w ith disease in 2 affected relatives (Boehmer 1999, Castro 2012). This variant is located in the 5' splice region. Studies on RNA isolated from patients demonstr ated that the c.277+4A>T variant leads to impaired splicing and reduced HSD17B3 transcript levels (Boehmer 1999). This variant has also been identified 0.04% (4 5/116,062) of chromosomes by the Exome Aggregation Consortium (ExAC, http://exac .broadinstitute.org; dbSNP 201115371). Although this variant has been seen in th e general population, its frequency is low enough to be consistent with a recess ive carrier frequency. In summary, the c.277+4A>T variant meets our criteria to be classified as pathogenic for 17 beta-hydroxysteroid dehydrogenase 3 deficienc y in an autosomal recessive manner based upon its identification and segregation in affected individuals, low frequency in controls, and functional evidence. -

May 17, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3 PM3_Strong -

Jan 03, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 07, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Across a selection of the available literature, the HSD17B3 c.277+4A>T variant has been identified in a homozygous state in at least nine probands and in a compound heterozygous state in eleven probands (Andersson et al. 1996; Boehmer et al. 1999; Mains et al. 2008; Castro et al. 2012). Additionally, Boehmer et al. (1999) performed transcript analysis of a homozygous patient that showed the c.277+4A>T variant results in skipping of exon three of HSD17B3. The c.277+4A>T variant was absent from 200 control subjects and is reported at a frequency of 0.000703 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence, the c.277+4A>T 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. -

not provided Pathogenic:4

Oct 05, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 07, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Non-canonical splice site variant demonstrated to result in loss-of-function (Boehmer et al., 1999); This variant is associated with the following publications: (PMID: 25525159, 10599740, 27951541, 30609409, 30668521, 25740850, 32297288, 34426522, 31589614) -

Jun 19, 2020

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change is in the canonical splice donor site of intron 3, c.277+4A>T. This sequence change has been described in the gnomAD database with a population frequency of 0.068% in the non-Finnish European subpopulation (dbSNP rs201115371). This sequence change has previously been described in both homozygous and compound heterozygous states in multiple patients with 17 Beta-hydroxysteroid dehydrogenase 3 deficiency (PMIDs: 27951541, 25740850, 8550739, 10599740). RNA studies have shown that this variant affects normal splicing and results in reduced levels of HSD17B3 transcripts with deletion of exon 3 (PMID: 10599740). These collective evidences indicate that this sequence change is pathogenic. -

Dec 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 3 of the HSD17B3 gene. It does not directly change the encoded amino acid sequence of the HSD17B3 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs201115371, gnomAD 0.07%). This variant has been observed in individuals with 17-beta hydroxysteroid dehydrogenase 3 deficiency (PMID: 10599740, 25740850, 32297288). This variant is also known as 325+4A>T. ClinVar contains an entry for this variant (Variation ID: 208587). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 3, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 10599740). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Mar 21, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.277+4A>T intronic alteration results from an A to T substitution 4 nucleotides after coding exon 3 of the HSD17B3 gene. Based on data from gnomAD, the T allele has an overall frequency of 0.033% (94/282304) total alleles studied. The highest observed frequency was 0.068% (88/128990) of European (non-Finnish) alleles. This variant has been identified in the homozygous state and in conjunction with other HSD17B3 variants in individuals with features consistent with 17-beta-hydroxysteroid dehydrogenase deficiency; in at least one instance, the variants were identified in trans (Boehmer, 1999; Phelan, 2015; Hughes, 2019; Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. Studies of RNA splicing in an individual homozygous for this variant revealed that no wild type transcript was produced. Instead, a transcript with deletion of exon 3 and a transcript with deletion of exons 3 and 4 were detected. These transcripts resulted in loss of function (Boehmer, 1999). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic. -

Pseudohermaphroditism Pathogenic:1

Jul 31, 2015

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

HSD17B3-related disorder Pathogenic:1

Mar 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The HSD17B3 c.277+4A>T variant is predicted to interfere with splicing. This variant has been reported to be causative in multiple patients with 17-beta hydroxysteroid dehydrogenase deficiency-related male pesudohermaphroditism when present in the homozygous state or in the compound heterozygous state with a second HSD17B3 pathogenic variant (Boehmer et al. 1999. PubMed ID: 10599740, reported as c.325+4A>T; Phelan et al. 2015. PubMed ID: 25740850). This variant is reported in 0.068% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Benign	0.95
PhyloP100		4.3
Mutation Taster		=26/74	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.66		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.66		Position offset: 4

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

Other links and lift over

dbSNP: rs201115371; hg19: chr9-99017146;