rs2066474

Variant names:

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

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.-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
• Publications: 8 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000285269 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B3	NM_000197.2	MANE Select	c.-39A>G		5_prime_UTR	Exon 1 of 11	NP_000188.1	P37058-1
	SLC35D2-HSD17B3	NR_182427.1		n.2729A>G		non_coding_transcript_exon	Exon 16 of 26

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B3	ENST00000375263.8	TSL:1 MANE Select	c.-39A>G		5_prime_UTR	Exon 1 of 11	ENSP00000364412.3	P37058-1
	ENSG00000285269	ENST00000643789.1		n.*1638A>G		non_coding_transcript_exon	Exon 12 of 22	ENSP00000494818.1	A0A2R8Y5X9
	ENSG00000285269	ENST00000643789.1		n.*1638A>G		3_prime_UTR	Exon 12 of 22	ENSP00000494818.1	A0A2R8Y5X9

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Testosterone 17-beta-dehydrogenase deficiency (1)

Computational scores

Source: dbNSFP v4.9

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2066474;

hg19: chr9-99064425;

COSMIC: COSV64556740;