chr1-119419555-G-A

Variant names:

• chr1-119419555-G-A
• rs6211
• NM_000198.4:c.280G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000198.4(HSD3B2):​c.280G>A​(p.Glu94Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. E94Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HSD3B2 NM_000198.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.58
• 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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3285361).

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.280G>A	p.Glu94Lys	missense	Exon 3 of 4	NP_000189.1	P26439-1
	HSD3B2	NM_001166120.2		c.280G>A	p.Glu94Lys	missense	Exon 3 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.280G>A	p.Glu94Lys	missense	Exon 3 of 4	ENSP00000358424.3	P26439-1
	HSD3B2	ENST00000543831.5	TSL:3	c.280G>A	p.Glu94Lys	missense	Exon 3 of 4	ENSP00000445122.1	P26439-1
	HSD3B2	ENST00000902254.1		c.280G>A	p.Glu94Lys	missense	Exon 2 of 3	ENSP00000572313.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461622 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727126

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111842

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.0014	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	8.2
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	2.0	M
PhyloP100		1.6
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.17
Sift	Benign	0.071	T
Sift4G	Benign	0.27	T
Polyphen		0.17	B
Vest4		0.17
MutPred		0.37		Gain of methylation at E94 (P = 0.0127)
MVP		0.86
MPC		0.64
ClinPred		0.60	D
GERP RS		1.8
Varity_R		0.10
gMVP		0.38
Mutation Taster		=96/4	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: rs6211; hg19: chr1-119962178; COSMIC: COSV65593164;