1-119422165-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_000198.4(HSD3B2):c.664C>G(p.Pro222Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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)
• Consequence: HSD3B2 NM_000198.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 Likely_pathogenic. Variant got 8 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, 0.947

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSD3B2	NM_000198.4	c.664C>G	p.Pro222Ala	missense_variant	4/4	ENST00000369416.4
HSD3B2	NM_001166120.2	c.664C>G	p.Pro222Ala	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSD3B2	ENST00000369416.4	c.664C>G	p.Pro222Ala	missense_variant	4/4	1	NM_000198.4	P1
HSD3B2	ENST00000543831.5	c.664C>G	p.Pro222Ala	missense_variant	4/4	3		P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251214 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135762

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D;D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;.
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Pathogenic	2.9	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-6.2	D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0050	D;D
Sift4G	Benign	0.067	T;T
Polyphen		1.0	D;D
Vest4		0.71
MutPred		0.83		Loss of stability (P = 0.1276);Loss of stability (P = 0.1276);
MVP		1.0
MPC		0.84
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.60
gMVP		0.56

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;