rs2066486

Variant names:

• chr9-96244296-T-C
• rs2066486
• NM_000197.2:c.672+33A>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.672+33A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 1,608,480 control chromosomes in the GnomAD database, including 56,594 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5529 hom., cov: 32)
  • Exomes 𝑓: 0.26 (51065 hom.)
• Consequence: HSD17B3 NM_000197.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.308
• Publications: 5 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 (BayesDel_noAF=-0.85).
• BP6: Variant 9-96244296-T-C is Benign according to our data. Variant chr9-96244296-T-C is described in ClinVar as Benign. ClinVar VariationId is 255510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B3	NM_000197.2	c.672+33A>G		intron_variant	Intron 9 of 10	ENST00000375263.8	NP_000188.1
SLC35D2-HSD17B3	NR_182427.1	n.3439+33A>G		intron_variant	Intron 24 of 25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD17B3	ENST00000375263.8	c.672+33A>G		intron_variant	Intron 9 of 10	1	NM_000197.2	ENSP00000364412.3
ENSG00000285269	ENST00000643789.1	n.*2348+33A>G		intron_variant	Intron 20 of 21			ENSP00000494818.1

Frequencies

GnomAD3 genomes AF: 0.263 AC: 39993 AN: 151978 Hom.: 5524 Cov.: 32

Gnomad AFR AF: 0.302

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.0284

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.287

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.275

Gnomad OTH AF: 0.256

GnomAD2 exomes AF: 0.223 AC: 56111 AN: 251464 AF XY: 0.223

Gnomad AFR exome AF: 0.309

Gnomad AMR exome AF: 0.127

Gnomad ASJ exome AF: 0.289

Gnomad EAS exome AF: 0.0278

Gnomad FIN exome AF: 0.282

Gnomad NFE exome AF: 0.276

Gnomad OTH exome AF: 0.253

GnomAD4 exome AF: 0.256 AC: 373402 AN: 1456384 Hom.: 51065 Cov.: 30 AF XY: 0.253 AC XY: 183418 AN XY: 724952

African (AFR) AF: 0.311 AC: 10374 AN: 33360

American (AMR) AF: 0.136 AC: 6060 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 7435 AN: 26108

East Asian (EAS) AF: 0.0220 AC: 873 AN: 39680

South Asian (SAS) AF: 0.141 AC: 12181 AN: 86154

European-Finnish (FIN) AF: 0.282 AC: 15071 AN: 53408

Middle Eastern (MID) AF: 0.344 AC: 1979 AN: 5760

European-Non Finnish (NFE) AF: 0.275 AC: 304451 AN: 1106992

Other (OTH) AF: 0.249 AC: 14978 AN: 60200

GnomAD4 genome AF: 0.263 AC: 40032 AN: 152096 Hom.: 5529 Cov.: 32 AF XY: 0.257 AC XY: 19120 AN XY: 74344

African (AFR) AF: 0.302 AC: 12539 AN: 41488

American (AMR) AF: 0.205 AC: 3134 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 965 AN: 3470

East Asian (EAS) AF: 0.0284 AC: 147 AN: 5168

South Asian (SAS) AF: 0.131 AC: 634 AN: 4822

European-Finnish (FIN) AF: 0.287 AC: 3031 AN: 10568

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.275 AC: 18667 AN: 67984

Other (OTH) AF: 0.256 AC: 541 AN: 2112

Alfa AF: 0.267 Hom.: 1883

Bravo AF: 0.259

Asia WGS AF: 0.106 AC: 370 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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 08, 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.2
DANN	Benign	0.66
PhyloP100		0.31
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: rs2066486; hg19: chr9-99006578; COSMIC: COSV64556191; COSMIC: COSV64556191;