rs80358220

Positions:

• chr1-119422165-C-A
• chr1-119422165-C-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000198.4(HSD3B2):​c.664C>A​(p.Pro222Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,814 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P222Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HSD3B2 NM_000198.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.09

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 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-119422166-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1722337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 1-119422165-C-A is Pathogenic according to our data. Variant chr1-119422165-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 12191.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	c.664C>A	p.Pro222Thr	missense_variant	4/4	ENST00000369416.4	NP_000189.1
HSD3B2	NM_001166120.2	c.664C>A	p.Pro222Thr	missense_variant	4/4		NP_001159592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSD3B2	ENST00000369416.4	c.664C>A	p.Pro222Thr	missense_variant	4/4	1	NM_000198.4	ENSP00000358424.3
HSD3B2	ENST00000543831.5	c.664C>A	p.Pro222Thr	missense_variant	4/4	3		ENSP00000445122.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461814 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727214

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000882 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

3 beta-Hydroxysteroid dehydrogenase deficiency Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 06, 2021	- -

Congenital adrenal hyperplasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jun 29, 2022

Variant summary: HSD3B2 c.664C>A (p.Pro222Thr) results in a non-conservative amino acid change located in the 3-beta hydroxysteroid dehydrogenase/isomerase domain (IPR002225) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251214 control chromosomes. c.664C>A has been reported in the literature as a homozygous genotype in at-least two individuals affected with classic salt wasting phenotype of 3-beta-hydroxysteroid dehydrogenase deficiency Congenital Adrenal Hyperplasia with subsequent citations by others (example, Pang_2002, Lutfallah_2002, Baquedano_2018, Baronio_2019, Al Alawi_2019, Guran_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Pang_2002). The most pronounced variant effect results in undetectable levels of normal enzyme activity in vitro using pregnenolone and dehydroepiandrosterone as substrates. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and 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
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T;.
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	1.9	L;L
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-6.3	D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;D
Sift4G	Benign	0.072	T;T
Polyphen		1.0	D;D
Vest4		0.84
MutPred		0.92		Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);
MVP		1.0
MPC		0.69
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.82
gMVP		0.68

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: rs80358220; hg19: chr1-119964788;