rs80358219
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Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate
The NM_000198.4(HSD3B2):c.424G>A(p.Glu142Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,912 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 Pathogenic (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000015 ( 0 hom. )
Consequence
HSD3B2
NM_000198.4 missense
NM_000198.4 missense
Scores
11
6
2
Clinical Significance
Conservation
PhyloP100: 9.23
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.939
PP5
Variant 1-119421925-G-A is Pathogenic according to our data. Variant chr1-119421925-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 12190.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HSD3B2 | NM_000198.4 | c.424G>A | p.Glu142Lys | missense_variant | 4/4 | ENST00000369416.4 | |
HSD3B2 | NM_001166120.2 | c.424G>A | p.Glu142Lys | missense_variant | 4/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HSD3B2 | ENST00000369416.4 | c.424G>A | p.Glu142Lys | missense_variant | 4/4 | 1 | NM_000198.4 | P1 | |
HSD3B2 | ENST00000543831.5 | c.424G>A | p.Glu142Lys | missense_variant | 4/4 | 3 | P1 | ||
HSD3B2 | ENST00000433745.5 | c.424G>A | p.Glu142Lys | missense_variant | 4/4 | 3 | |||
HSD3B2 | ENST00000448448.2 | n.368G>A | non_coding_transcript_exon_variant | 3/3 | 5 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152074Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251142Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135714
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GnomAD4 exome AF: 0.0000150 AC: 22AN: 1461838Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 727224
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GnomAD4 genome AF: 0.00000658 AC: 1AN: 152074Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74286
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
3 beta-Hydroxysteroid dehydrogenase deficiency Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2002 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 02, 2020 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 30, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 142 of the HSD3B2 protein (p.Glu142Lys). This variant is present in population databases (rs80358219, gnomAD 0.003%). This missense change has been observed in individual(s) with congenital adrenal hyperplasia (PMID: 8316254, 12050213, 27796263). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 12190). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HSD3B2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects HSD3B2 function (PMID: 8316254, 11196452). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;.
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;H
MutationTaster
Benign
A;A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;.;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at