1-119422941-C-G

Variant names:

• chr1-119422941-C-G
• rs1361530
• NM_000198.4:c.*321C>G

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.*321C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.166 in 470,306 control chromosomes in the GnomAD database, including 8,433 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3645 hom., cov: 32)
  • Exomes 𝑓: 0.15 (4788 hom.)
• Consequence: HSD3B2 NM_000198.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.632
• Publications: 5 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=-0.88).
• BP6: Variant 1-119422941-C-G is Benign according to our data. Variant chr1-119422941-C-G is described in ClinVar as Benign. ClinVar VariationId is 292275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.337 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD3B2	NM_000198.4	c.*321C>G		3_prime_UTR_variant	Exon 4 of 4	ENST00000369416.4	NP_000189.1
HSD3B2	NM_001166120.2	c.*321C>G		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.*321C>G		3_prime_UTR_variant	Exon 4 of 4	1	NM_000198.4	ENSP00000358424.3
HSD3B2	ENST00000543831.5	c.*321C>G		3_prime_UTR_variant	Exon 4 of 4	3		ENSP00000445122.1

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29198 AN: 152170 Hom.: 3633 Cov.: 32

Gnomad AFR AF: 0.341

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.252

Gnomad SAS AF: 0.255

Gnomad FIN AF: 0.0871

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.197

GnomAD4 exome AF: 0.153 AC: 48613 AN: 318018 Hom.: 4788 Cov.: 0 AF XY: 0.157 AC XY: 25969 AN XY: 165156

African (AFR) AF: 0.339 AC: 3487 AN: 10292

American (AMR) AF: 0.176 AC: 2062 AN: 11710

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 2132 AN: 10768

East Asian (EAS) AF: 0.322 AC: 7050 AN: 21886

South Asian (SAS) AF: 0.243 AC: 8557 AN: 35164

European-Finnish (FIN) AF: 0.0874 AC: 1334 AN: 15258

Middle Eastern (MID) AF: 0.223 AC: 316 AN: 1414

European-Non Finnish (NFE) AF: 0.108 AC: 20848 AN: 192506

Other (OTH) AF: 0.149 AC: 2827 AN: 19020

GnomAD4 genome AF: 0.192 AC: 29251 AN: 152288 Hom.: 3645 Cov.: 32 AF XY: 0.194 AC XY: 14476 AN XY: 74476

African (AFR) AF: 0.341 AC: 14175 AN: 41538

American (AMR) AF: 0.189 AC: 2891 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 749 AN: 3468

East Asian (EAS) AF: 0.252 AC: 1305 AN: 5180

South Asian (SAS) AF: 0.254 AC: 1227 AN: 4830

European-Finnish (FIN) AF: 0.0871 AC: 925 AN: 10614

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.107 AC: 7292 AN: 68028

Other (OTH) AF: 0.198 AC: 418 AN: 2114

Alfa AF: 0.0589 Hom.: 74

Bravo AF: 0.206

Asia WGS AF: 0.258 AC: 900 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

3 beta-Hydroxysteroid dehydrogenase deficiency Benign:1

Jan 13, 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	-0.88
CADD	Benign	0.94
DANN	Benign	0.84
PhyloP100		-0.63
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: rs1361530; hg19: chr1-119965564;