rs1819698

Positions:

• chr1-119422896-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000198.4(HSD3B2):​c.*276C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 542,030 control chromosomes in the GnomAD database, including 13,753 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (6746 hom., cov: 32)
  • Exomes 𝑓: 0.16 (7007 hom.)
• Consequence: HSD3B2 NM_000198.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.682

Genes affected

HSD3B2 (HGNC:5218): (hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 2) The protein encoded by this gene is a bifunctional enzyme that catalyzes the oxidative conversion of delta(5)-ene-3-beta-hydroxy steroid, and the oxidative conversion of ketosteroids. It plays a crucial role in the biosynthesis of all classes of hormonal steroids. This gene is predominantly expressed in the adrenals and the gonads. Mutations in this gene are associated with 3-beta-hydroxysteroid dehydrogenase, type II, deficiency. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BP6: Variant 1-119422896-C-T is Benign according to our data. Variant chr1-119422896-C-T is described in ClinVar as [Benign]. Clinvar id is 292274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.504 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSD3B2	NM_000198.4	c.*276C>T		3_prime_UTR_variant	4/4	ENST00000369416.4
HSD3B2	NM_001166120.2	c.*276C>T		3_prime_UTR_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSD3B2	ENST00000369416.4	c.*276C>T		3_prime_UTR_variant	4/4	1	NM_000198.4	P1
HSD3B2	ENST00000543831.5	c.*276C>T		3_prime_UTR_variant	4/4	3		P1

Frequencies

GnomAD3 genomes AF: 0.243 AC: 36940 AN: 152002 Hom.: 6732 Cov.: 32

Gnomad AFR AF: 0.510

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.210

Gnomad ASJ AF: 0.226

Gnomad EAS AF: 0.253

Gnomad SAS AF: 0.257

Gnomad FIN AF: 0.0886

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.234

GnomAD4 exome AF: 0.164 AC: 64105 AN: 389914 Hom.: 7007 Cov.: 2 AF XY: 0.167 AC XY: 34378 AN XY: 205274

Gnomad4 AFR exome AF: 0.504

Gnomad4 AMR exome AF: 0.195

Gnomad4 ASJ exome AF: 0.212

Gnomad4 EAS exome AF: 0.327

Gnomad4 SAS exome AF: 0.252

Gnomad4 FIN exome AF: 0.0888

Gnomad4 NFE exome AF: 0.115

Gnomad4 OTH exome AF: 0.170

GnomAD4 genome AF: 0.243 AC: 36999 AN: 152116 Hom.: 6746 Cov.: 32 AF XY: 0.244 AC XY: 18118 AN XY: 74376

Gnomad4 AFR AF: 0.510

Gnomad4 AMR AF: 0.210

Gnomad4 ASJ AF: 0.226

Gnomad4 EAS AF: 0.254

Gnomad4 SAS AF: 0.256

Gnomad4 FIN AF: 0.0886

Gnomad4 NFE AF: 0.112

Gnomad4 OTH AF: 0.234

Alfa AF: 0.187 Hom.: 695

Bravo AF: 0.264

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 08, 2018

- -

3 beta-Hydroxysteroid dehydrogenase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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	-1.0
CADD	Benign	3.2
DANN	Benign	0.42

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

Publications

LitVar

Other links and lift over

dbSNP: rs1819698; hg19: chr1-119965519;