Variant 1-119422317-CAA-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_000198.4(HSD3B2):c.818_819del(p.Lys273ArgfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

HSD3B2
NM_000198.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 2.26

Variant links:

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]

HSD3B2 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 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. There are 6 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-119422317-CAA-C is Pathogenic according to our data. Variant chr1-119422317-CAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 586031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSD3B2	NM_000198.4 linkuse as main transcript	c.818_819del	p.Lys273ArgfsTer7	frameshift_variant	4/4	ENST00000369416.4	NP_000189.1
HSD3B2	NM_001166120.2 linkuse as main transcript	c.818_819del	p.Lys273ArgfsTer7	frameshift_variant	4/4		NP_001159592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSD3B2	ENST00000369416.4 linkuse as main transcript	c.818_819del	p.Lys273ArgfsTer7	frameshift_variant	4/4	1	NM_000198.4	ENSP00000358424	P1	P26439-1
HSD3B2	ENST00000543831.5 linkuse as main transcript	c.818_819del	p.Lys273ArgfsTer7	frameshift_variant	4/4	3		ENSP00000445122	P1	P26439-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251282

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135810

show subpopulations

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:

0.000261

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461840

Hom.:

AF XY:

0.0000138

AC XY:

AN XY:

727226

show subpopulations

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:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 27, 2023	This sequence change creates a premature translational stop signal (p.Lys273Argfs7) in the HSD3B2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 100 amino acid(s) of the HSD3B2 protein. This variant is present in population databases (rs754609778, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with 3-beta-hydroxysteroid dehydrogenase deficiency (PMID: 8004103). This variant is also known as 273deltaAA. ClinVar contains an entry for this variant (Variation ID: 586031). This variant disrupts a region of the HSD3B2 protein in which other variant(s) (p.Arg335) have been determined to be pathogenic (PMID: 18252794, 31006099). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 15, 2017	- -

3 beta-Hydroxysteroid dehydrogenase deficiency

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Biochemistry Laboratory, Health Services Laboratory

Nov 20, 2023

ACMG:PVS1 PM2 PP3 PP4 -

Congenital adrenal hyperplasia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Nov 15, 2022

Variant summary: HSD3B2 c.818_819delAA (p.Lys273ArgfsX7) results in a premature termination codon, which is predicted to cause a truncation of the encoded protein. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.2e-05 in 251282 control chromosomes (gnomAD). c.818_819delAA has been reported in the literature in multiple individuals affected with Congenital Adrenal Hyperplasia (e.g. Chang_1995, Simard_1994, Marui_2000, Leka-Emiri_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over