ENST00000902254.1:c.-273G>A

Variant names:

• chr1-119415147-G-A
• rs35226381
• ENST00000902254.1:c.-273G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000902254.1(HSD3B2):​c.-273G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00296 in 441,222 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0069 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00091 (2 hom.)
• Consequence: HSD3B2 ENST00000902254.1 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.772
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-119415147-G-A is Benign according to our data. Variant chr1-119415147-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 292254.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00685 (1044/152326) while in subpopulation AFR AF = 0.0239 (994/41558). AF 95% confidence interval is 0.0227. There are 12 homozygotes in GnomAd4. There are 474 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000902254.1. 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_001166120.2		c.-90+57G>A		intron	N/A	NP_001159592.1	P26439-1
	HSD3B2	NM_000198.4	MANE Select	c.-145G>A		upstream_gene	N/A	NP_000189.1	P26439-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD3B2	ENST00000902254.1		c.-273G>A		5_prime_UTR	Exon 1 of 3	ENSP00000572313.1
	HSD3B2	ENST00000948747.1		c.-98G>A		5_prime_UTR	Exon 1 of 4	ENSP00000618806.1
	HSD3B2	ENST00000543831.5	TSL:3	c.-90+57G>A		intron	N/A	ENSP00000445122.1	P26439-1

Frequencies

GnomAD3 genomes AF: 0.00685 AC: 1042 AN: 152208 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0239

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00382

GnomAD4 exome AF: 0.000907 AC: 262 AN: 288896 Hom.: 2 Cov.: 0 AF XY: 0.000673 AC XY: 104 AN XY: 154642

African (AFR) AF: 0.0236 AC: 202 AN: 8566

American (AMR) AF: 0.00196 AC: 27 AN: 13770

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8584

East Asian (EAS) AF: 0.00 AC: 0 AN: 17652

South Asian (SAS) AF: 0.0000235 AC: 1 AN: 42572

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11984

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1170

European-Non Finnish (NFE) AF: 0.0000356 AC: 6 AN: 168616

Other (OTH) AF: 0.00163 AC: 26 AN: 15982

GnomAD4 genome AF: 0.00685 AC: 1044 AN: 152326 Hom.: 12 Cov.: 32 AF XY: 0.00636 AC XY: 474 AN XY: 74496

African (AFR) AF: 0.0239 AC: 994 AN: 41558

American (AMR) AF: 0.00242 AC: 37 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68024

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00527 Hom.: 1

Bravo AF: 0.00782

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital adrenal hyperplasia (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.016
DANN	Benign	0.36
PhyloP100		-0.77
PromoterAI		0.027	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs35226381; hg19: chr1-119957770;