chr1-119415441-A-G

Position:

• chr1-119415441-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000198.4(HSD3B2):​c.22A>G​(p.Thr8Ala) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HSD3B2 NM_000198.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.99

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSD3B2	NM_000198.4	c.22A>G	p.Thr8Ala	missense_variant	2/4	ENST00000369416.4	NP_000189.1
HSD3B2	NM_001166120.2	c.22A>G	p.Thr8Ala	missense_variant	2/4		NP_001159592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSD3B2	ENST00000369416.4	c.22A>G	p.Thr8Ala	missense_variant	2/4	1	NM_000198.4	ENSP00000358424	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 14, 2024

The c.22A>G (p.T8A) alteration is located in exon 2 (coding exon 1) of the HSD3B2 gene. This alteration results from a A to G substitution at nucleotide position 22, causing the threonine (T) at amino acid position 8 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;D;D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.58	T;T;.
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.8	H;.;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.1	D;D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.035	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.85
MutPred		0.76		Loss of MoRF binding (P = 0.1708);Loss of MoRF binding (P = 0.1708);Loss of MoRF binding (P = 0.1708);
MVP		1.0
MPC		0.87
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.92
gMVP		0.61

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-119958064;