rs2066474

Variant names:

• chr9-96302143-T-C
• rs2066474
• NM_000197.2:c.-39A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000197.2(HSD17B3):​c.-39A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 1,606,212 control chromosomes in the GnomAD database, including 36,679 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3510 hom., cov: 31)
  • Exomes 𝑓: 0.20 (33169 hom.)
• Consequence: HSD17B3 NM_000197.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.252

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:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 9-96302143-T-C is Benign according to our data. Variant chr9-96302143-T-C is described in ClinVar as [Benign]. Clinvar id is 255507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B3	NM_000197.2	c.-39A>G		5_prime_UTR_variant	Exon 1 of 11	ENST00000375263.8	NP_000188.1
SLC35D2-HSD17B3	NR_182427.1	n.2729A>G		non_coding_transcript_exon_variant	Exon 16 of 26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD17B3	ENST00000375263.8	c.-39A>G		5_prime_UTR_variant	Exon 1 of 11	1	NM_000197.2	ENSP00000364412.3
ENSG00000285269	ENST00000643789.1	n.*1638A>G		non_coding_transcript_exon_variant	Exon 12 of 22			ENSP00000494818.1
ENSG00000285269	ENST00000643789.1	n.*1638A>G		3_prime_UTR_variant	Exon 12 of 22			ENSP00000494818.1

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31172 AN: 151904 Hom.: 3511 Cov.: 31

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.237

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.474

Gnomad SAS AF: 0.369

Gnomad FIN AF: 0.256

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.207

GnomAD3 exomes AF: 0.253 AC: 60253 AN: 238376 Hom.: 8745 AF XY: 0.255 AC XY: 32845 AN XY: 128738

Gnomad AFR exome AF: 0.172

Gnomad AMR exome AF: 0.276

Gnomad ASJ exome AF: 0.253

Gnomad EAS exome AF: 0.502

Gnomad SAS exome AF: 0.380

Gnomad FIN exome AF: 0.255

Gnomad NFE exome AF: 0.182

Gnomad OTH exome AF: 0.225

GnomAD4 exome AF: 0.201 AC: 292802 AN: 1454190 Hom.: 33169 Cov.: 32 AF XY: 0.207 AC XY: 149299 AN XY: 722948

Gnomad4 AFR exome AF: 0.178

Gnomad4 AMR exome AF: 0.269

Gnomad4 ASJ exome AF: 0.256

Gnomad4 EAS exome AF: 0.457

Gnomad4 SAS exome AF: 0.373

Gnomad4 FIN exome AF: 0.254

Gnomad4 NFE exome AF: 0.172

Gnomad4 OTH exome AF: 0.220

GnomAD4 genome AF: 0.205 AC: 31199 AN: 152022 Hom.: 3510 Cov.: 31 AF XY: 0.214 AC XY: 15882 AN XY: 74302

Gnomad4 AFR AF: 0.171

Gnomad4 AMR AF: 0.238

Gnomad4 ASJ AF: 0.241

Gnomad4 EAS AF: 0.473

Gnomad4 SAS AF: 0.368

Gnomad4 FIN AF: 0.256

Gnomad4 NFE AF: 0.177

Gnomad4 OTH AF: 0.206

Alfa AF: 0.191 Hom.: 1430

Bravo AF: 0.203

Asia WGS AF: 0.362 AC: 1258 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 25, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Testosterone 17-beta-dehydrogenase deficiency Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.7
DANN	Benign	0.63

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

Other links and lift over

dbSNP: rs2066474; hg19: chr9-99064425; COSMIC: COSV64556740;