1-119422565-G-A

Variant names:

• chr1-119422565-G-A
• rs767128094
• NM_000198.4:c.1064G>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000198.4(HSD3B2):​c.1064G>A​(p.Trp355*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HSD3B2 NM_000198.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.15

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0492 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-119422565-G-A is Pathogenic according to our data. Variant chr1-119422565-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 517183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD3B2	NM_000198.4	c.1064G>A	p.Trp355*	stop_gained	Exon 4 of 4	ENST00000369416.4	NP_000189.1
HSD3B2	NM_001166120.2	c.1064G>A	p.Trp355*	stop_gained	Exon 4 of 4		NP_001159592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD3B2	ENST00000369416.4	c.1064G>A	p.Trp355*	stop_gained	Exon 4 of 4	1	NM_000198.4	ENSP00000358424.3
HSD3B2	ENST00000543831.5	c.1064G>A	p.Trp355*	stop_gained	Exon 4 of 4	3		ENSP00000445122.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250916 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135614

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461768 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

3 beta-Hydroxysteroid dehydrogenase deficiency Pathogenic:2

Dec 19, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Trp355X variant in HSD3B2 has been reported in a homozygous individual wit h clinical features of 3-beta (?)-hydroxysteroid dehydrogenase (HSD) deficiency (Welzel 2008). The p.Trp355X variant has been identified in 1/6498 of South Asia n chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstit ute.org; dbSNP rs767128094). This nonsense variant leads to a premature terminat ion codon at position 355, which is predicted to lead to a truncated or absent p rotein. Biallelic loss of function of the HSD3B2 gene has been associated with H SD deficiency. In vitro studies provide evidence that this variant leads to a tr uncated protein which impacts protein function (Welzel 2008). However, these typ es of assays may not accurately represent biological function. In summary, alth ough additional studies are required to fully establish a null effect on the pro tein, the p.Trp355X variant in HSD3B2 is likely pathogenic for 3-beta (?)-hydrox ysteroid dehydrogenase (HSD) deficiency in an autosomal recessive manner based u pon its predicted impact on protein function. -

May 31, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital adrenal hyperplasia Pathogenic:1

Sep 26, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HSD3B2 c.1064G>A (p.Trp355X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been in association with Adrenal hyperplasia and 3 beta-hydroxysteroid dehydrogenase deficiency in HGMD. The variant allele was found at a frequency of 8e-06 in 250916 control chromosomes. c.1064G>A has been reported in the literature in an individual affected with Congenital Adrenal Hyperplasia (Welzel_2008). These data indicate that the variant is likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein expression and enzymatic activity, resulting in <10% of normal activity and no or very little protein expression in the absence of a proteasome inhibitor (Welzel_2008). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.85
GERP RS		4.3

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: rs767128094; hg19: chr1-119965188;