NM_000198.4:c.22A>G

Variant names:

• chr1-119415441-A-G
• rs1651676376
• NM_000198.4:c.22A>G

Variant summary

Our verdict is Uncertain significance. The variant received 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 (★). Synonymous variant affecting the same amino acid position (i.e. T8T) has been classified as Likely benign.

• 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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• congenital adrenal hyperplasia due to 3-beta-hydroxysteroid dehydrogenase deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000307032 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000198.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD3B2	NM_000198.4	MANE Select	c.22A>G	p.Thr8Ala	missense	Exon 2 of 4	NP_000189.1	P26439-1
	HSD3B2	NM_001166120.2		c.22A>G	p.Thr8Ala	missense	Exon 2 of 4	NP_001159592.1	P26439-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD3B2	ENST00000369416.4	TSL:1 MANE Select	c.22A>G	p.Thr8Ala	missense	Exon 2 of 4	ENSP00000358424.3	P26439-1
	HSD3B2	ENST00000543831.5	TSL:3	c.22A>G	p.Thr8Ala	missense	Exon 2 of 4	ENSP00000445122.1	P26439-1
	HSD3B2	ENST00000902254.1		c.22A>G	p.Thr8Ala	missense	Exon 1 of 3	ENSP00000572313.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.58	T
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		5.0
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.1	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.035	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.76		Loss of MoRF binding (P = 0.1708)
MVP		1.0
MPC		0.87
ClinPred		1.0	D
GERP RS		3.6
PromoterAI		-0.11	Neutral
Varity_R		0.92
gMVP		0.61
Mutation Taster		=55/45	polymorphism

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

Other links and lift over

dbSNP: rs1651676376; hg19: chr1-119958064;