rs12552648

Variant names:

• chr9-96239213-C-T
• rs12552648
• NM_000197.2:c.822+1545G>A

Variant summary

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

The NM_000197.2(HSD17B3):​c.822+1545G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0628 in 152,456 control chromosomes in the GnomAD database, including 439 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 0.063 (439 hom., cov: 32)
  • Exomes 𝑓: 0.031 (0 hom.)
• Consequence: HSD17B3 NM_000197.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.14
• Publications: 3 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ENSG00000285269 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.228 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.822+1545G>A		intron	N/A	NP_000188.1	P37058-1
	SLC35D2-HSD17B3	NR_182427.1		n.3589+1545G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B3	ENST00000375263.8	TSL:1 MANE Select	c.822+1545G>A		intron	N/A	ENSP00000364412.3	P37058-1
	HSD17B3	ENST00000375262.4	TSL:1	c.673-3643G>A		intron	N/A	ENSP00000364411.2	P37058-2
	ENSG00000285269	ENST00000643789.1		n.*2498+1545G>A		intron	N/A	ENSP00000494818.1	A0A2R8Y5X9

Frequencies

GnomAD3 genomes AF: 0.0629 AC: 9565 AN: 152112 Hom.: 441 Cov.: 32

Gnomad AFR AF: 0.0618

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.0533

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.239

Gnomad SAS AF: 0.0766

Gnomad FIN AF: 0.0465

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0497

Gnomad OTH AF: 0.0803

GnomAD4 exome AF: 0.0310 AC: 7 AN: 226 Hom.: 0 AF XY: 0.0325 AC XY: 5 AN XY: 154

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 6

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.250 AC: 1 AN: 4

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AF: 0.0405 AC: 3 AN: 74

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0246 AC: 3 AN: 122

Other (OTH) AF: 0.00 AC: 0 AN: 16

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00148735), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0628 AC: 9563 AN: 152230 Hom.: 439 Cov.: 32 AF XY: 0.0637 AC XY: 4739 AN XY: 74434

African (AFR) AF: 0.0619 AC: 2573 AN: 41534

American (AMR) AF: 0.0530 AC: 811 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 427 AN: 3470

East Asian (EAS) AF: 0.239 AC: 1235 AN: 5174

South Asian (SAS) AF: 0.0764 AC: 368 AN: 4814

European-Finnish (FIN) AF: 0.0465 AC: 493 AN: 10602

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.0497 AC: 3378 AN: 68018

Other (OTH) AF: 0.0790 AC: 167 AN: 2114

Alfa AF: 0.0488 Hom.: 30

Bravo AF: 0.0653

Asia WGS AF: 0.144 AC: 503 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.23
DANN	Benign	0.45
PhyloP100		-1.1
Mutation Taster		=100/0	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: rs12552648; hg19: chr9-99001495;