9-96302143-T-C

Variant names:

• chr9-96302143-T-C
• rs2066474
• ENST00000643789.1:n.*1638A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000643789.1(ENSG00000285269):​n.*1638A>G variant causes a non coding transcript exon 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.21 (3510 hom., cov: 31)
  • Exomes 𝑓: 0.20 (33169 hom.)
• Consequence: ENSG00000285269 ENST00000643789.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.252
• Publications: 8 publications found

Genes affected

ENSG00000285269 (HGNC:):

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)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• 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
ENSG00000285269	ENST00000643789.1	n.*1638A>G		non_coding_transcript_exon_variant	Exon 12 of 22			ENSP00000494818.1
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		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

GnomAD2 exomes AF: 0.253 AC: 60253 AN: 238376 AF XY: 0.255

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 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

African (AFR) AF: 0.178 AC: 5922 AN: 33188

American (AMR) AF: 0.269 AC: 11760 AN: 43728

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 6674 AN: 26028

East Asian (EAS) AF: 0.457 AC: 17921 AN: 39224

South Asian (SAS) AF: 0.373 AC: 31828 AN: 85302

European-Finnish (FIN) AF: 0.254 AC: 13487 AN: 53052

Middle Eastern (MID) AF: 0.243 AC: 1367 AN: 5624

European-Non Finnish (NFE) AF: 0.172 AC: 190652 AN: 1107966

Other (OTH) AF: 0.220 AC: 13191 AN: 60078

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

African (AFR) AF: 0.171 AC: 7092 AN: 41470

American (AMR) AF: 0.238 AC: 3628 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 835 AN: 3468

East Asian (EAS) AF: 0.473 AC: 2431 AN: 5136

South Asian (SAS) AF: 0.368 AC: 1773 AN: 4816

European-Finnish (FIN) AF: 0.256 AC: 2711 AN: 10570

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.177 AC: 12059 AN: 67974

Other (OTH) AF: 0.206 AC: 435 AN: 2110

Alfa AF: 0.189 Hom.: 4941

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
PhyloP100		0.25
PromoterAI		-0.013	Neutral
Mutation Taster		=298/2	polymorphism (auto)

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

Other links and lift over

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