1-119422896-C-T

Variant names:

• chr1-119422896-C-T
• rs1819698
• NM_000198.4:c.*276C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000198.4(HSD3B2):​c.*276C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 542,030 control chromosomes in the GnomAD database, including 13,753 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (6746 hom., cov: 32)
  • Exomes 𝑓: 0.16 (7007 hom.)
• Consequence: HSD3B2 NM_000198.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.682
• Publications: 13 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: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BP6: Variant 1-119422896-C-T is Benign according to our data. Variant chr1-119422896-C-T is described in ClinVar as Benign. ClinVar VariationId is 292274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.504 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD3B2	NM_000198.4	c.*276C>T		3_prime_UTR_variant	Exon 4 of 4	ENST00000369416.4	NP_000189.1
HSD3B2	NM_001166120.2	c.*276C>T		3_prime_UTR_variant	Exon 4 of 4		NP_001159592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD3B2	ENST00000369416.4	c.*276C>T		3_prime_UTR_variant	Exon 4 of 4	1	NM_000198.4	ENSP00000358424.3
HSD3B2	ENST00000543831.5	c.*276C>T		3_prime_UTR_variant	Exon 4 of 4	3		ENSP00000445122.1

Frequencies

GnomAD3 genomes AF: 0.243 AC: 36940 AN: 152002 Hom.: 6732 Cov.: 32

Gnomad AFR AF: 0.510

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.210

Gnomad ASJ AF: 0.226

Gnomad EAS AF: 0.253

Gnomad SAS AF: 0.257

Gnomad FIN AF: 0.0886

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.234

GnomAD4 exome AF: 0.164 AC: 64105 AN: 389914 Hom.: 7007 Cov.: 2 AF XY: 0.167 AC XY: 34378 AN XY: 205274

African (AFR) AF: 0.504 AC: 5770 AN: 11446

American (AMR) AF: 0.195 AC: 3120 AN: 16002

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 2604 AN: 12284

East Asian (EAS) AF: 0.327 AC: 8714 AN: 26644

South Asian (SAS) AF: 0.252 AC: 10758 AN: 42630

European-Finnish (FIN) AF: 0.0888 AC: 1979 AN: 22296

Middle Eastern (MID) AF: 0.238 AC: 400 AN: 1678

European-Non Finnish (NFE) AF: 0.115 AC: 26893 AN: 234206

Other (OTH) AF: 0.170 AC: 3867 AN: 22728

GnomAD4 genome AF: 0.243 AC: 36999 AN: 152116 Hom.: 6746 Cov.: 32 AF XY: 0.244 AC XY: 18118 AN XY: 74376

African (AFR) AF: 0.510 AC: 21107 AN: 41408

American (AMR) AF: 0.210 AC: 3207 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 785 AN: 3466

East Asian (EAS) AF: 0.254 AC: 1313 AN: 5178

South Asian (SAS) AF: 0.256 AC: 1236 AN: 4822

European-Finnish (FIN) AF: 0.0886 AC: 940 AN: 10612

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.112 AC: 7641 AN: 68026

Other (OTH) AF: 0.234 AC: 496 AN: 2116

Alfa AF: 0.187 Hom.: 695

Bravo AF: 0.264

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 08, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

3 beta-Hydroxysteroid dehydrogenase deficiency Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	3.2
DANN	Benign	0.42
PhyloP100		0.68
Mutation Taster		=100/0	polymorphism (auto)

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: rs1819698; hg19: chr1-119965519;