9-96302014-C-T

Variant names:

• chr9-96302014-C-T
• rs2066480
• NM_000197.2:c.91G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000197.2(HSD17B3):​c.91G>A​(p.Val31Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,614,124 control chromosomes in the GnomAD database, including 352 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (29 hom., cov: 31)
  • Exomes 𝑓: 0.012 (323 hom.)
• Consequence: HSD17B3 NM_000197.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.34
• Publications: 19 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]

HSD17B3 Gene-Disease associations (from GenCC):

• 46,XY disorder of sex development due to 17-beta-hydroxysteroid dehydrogenase 3 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000285269 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019617677).
• BP6: Variant 9-96302014-C-T is Benign according to our data. Variant chr9-96302014-C-T is described in ClinVar as Benign. ClinVar VariationId is 367684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0554 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000197.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B3	NM_000197.2	MANE Select	c.91G>A	p.Val31Ile	missense	Exon 1 of 11	NP_000188.1
	SLC35D2-HSD17B3	NR_182427.1		n.2858G>A		non_coding_transcript_exon	Exon 16 of 26

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B3	ENST00000375263.8	TSL:1 MANE Select	c.91G>A	p.Val31Ile	missense	Exon 1 of 11	ENSP00000364412.3
	HSD17B3	ENST00000375262.4	TSL:1	c.91G>A	p.Val31Ile	missense	Exon 1 of 10	ENSP00000364411.2
	ENSG00000285269	ENST00000643789.1		n.*1767G>A		non_coding_transcript_exon	Exon 12 of 22	ENSP00000494818.1

Frequencies

GnomAD3 genomes AF: 0.0121 AC: 1838 AN: 152164 Hom.: 28 Cov.: 31

Gnomad AFR AF: 0.0121

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.00897

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.0566

Gnomad SAS AF: 0.0615

Gnomad FIN AF: 0.00461

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00727

Gnomad OTH AF: 0.0119

GnomAD2 exomes AF: 0.0177 AC: 4457 AN: 251448 AF XY: 0.0193

Gnomad AFR exome AF: 0.0119

Gnomad AMR exome AF: 0.00431

Gnomad ASJ exome AF: 0.00397

Gnomad EAS exome AF: 0.0644

Gnomad FIN exome AF: 0.00522

Gnomad NFE exome AF: 0.00753

Gnomad OTH exome AF: 0.0135

GnomAD4 exome AF: 0.0118 AC: 17210 AN: 1461842 Hom.: 323 Cov.: 33 AF XY: 0.0132 AC XY: 9617 AN XY: 727230

African (AFR) AF: 0.0109 AC: 366 AN: 33480

American (AMR) AF: 0.00537 AC: 240 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00386 AC: 101 AN: 26136

East Asian (EAS) AF: 0.0538 AC: 2137 AN: 39696

South Asian (SAS) AF: 0.0600 AC: 5175 AN: 86252

European-Finnish (FIN) AF: 0.00616 AC: 329 AN: 53420

Middle Eastern (MID) AF: 0.00589 AC: 34 AN: 5768

European-Non Finnish (NFE) AF: 0.00716 AC: 7964 AN: 1111974

Other (OTH) AF: 0.0143 AC: 864 AN: 60392

GnomAD4 genome AF: 0.0121 AC: 1842 AN: 152282 Hom.: 29 Cov.: 31 AF XY: 0.0128 AC XY: 956 AN XY: 74456

African (AFR) AF: 0.0122 AC: 507 AN: 41544

American (AMR) AF: 0.00895 AC: 137 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3470

East Asian (EAS) AF: 0.0567 AC: 293 AN: 5164

South Asian (SAS) AF: 0.0612 AC: 295 AN: 4822

European-Finnish (FIN) AF: 0.00461 AC: 49 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00728 AC: 495 AN: 68040

Other (OTH) AF: 0.0128 AC: 27 AN: 2116

Alfa AF: 0.00986 Hom.: 71

Bravo AF: 0.0119

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00908 AC: 40

ESP6500EA AF: 0.00767 AC: 66

ExAC AF: 0.0190 AC: 2309

Asia WGS AF: 0.0580 AC: 201 AN: 3478

EpiCase AF: 0.00671

EpiControl AF: 0.00717

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 04, 2018

GeneDx

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.49
DANN	Benign	0.25
DEOGEN2	Benign	0.081	T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.0024	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	-1.1	N
PhyloP100		-1.3
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.20
Sift	Benign	1.0	T
Sift4G	Benign	0.84	T
Polyphen		0.0	B
Vest4		0.033
MPC		0.13
ClinPred		0.0011	T
GERP RS		-9.6
PromoterAI		0.0056	Neutral
Varity_R		0.018
gMVP		0.35
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2066480; hg19: chr9-99064296; COSMIC: COSV64558824;