1-119422208-T-C

Position:

chr1-119422208-T-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The ENST00000369416.4(HSD3B2):c.707T>C(p.Leu236Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00238 in 1,614,096 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.012 ( 32 hom., cov: 31)

Exomes 𝑓: 0.0014 ( 40 hom. )

Consequence

HSD3B2
ENST00000369416.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 1.00

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in ENST00000369416.4

BP4

Computational evidence support a benign effect (MetaRNN=0.006784588).

BP6

Variant 1-119422208-T-C is Benign according to our data. Variant chr1-119422208-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36370.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.012 (1823/152276) while in subpopulation AFR AF= 0.0412 (1712/41550). AF 95% confidence interval is 0.0396. There are 32 homozygotes in gnomad4. There are 834 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSD3B2	NM_000198.4 linkuse as main transcript	c.707T>C	p.Leu236Ser	missense_variant	4/4	ENST00000369416.4	NP_000189.1
HSD3B2	NM_001166120.2 linkuse as main transcript	c.707T>C	p.Leu236Ser	missense_variant	4/4		NP_001159592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSD3B2	ENST00000369416.4 linkuse as main transcript	c.707T>C	p.Leu236Ser	missense_variant	4/4	1	NM_000198.4	ENSP00000358424	P1	P26439-1
HSD3B2	ENST00000543831.5 linkuse as main transcript	c.707T>C	p.Leu236Ser	missense_variant	4/4	3		ENSP00000445122	P1	P26439-1

Frequencies

GnomAD3 genomes

AF:

0.0120

AC:

1824

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0413

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00373

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.0100

GnomAD3 exomes

AF:

0.00304

AC:

762

AN:

250862

Hom.:

AF XY:

0.00225

AC XY:

305

AN XY:

135692

show subpopulations

Gnomad AFR exome

AF:

0.0419

Gnomad AMR exome

AF:

0.00113

Gnomad ASJ exome

AF:

0.000695

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000291

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00138

AC:

2021

AN:

1461820

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

875

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.0420

Gnomad4 AMR exome

AF:

0.00148

Gnomad4 ASJ exome

AF:

0.000918

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000277

Gnomad4 OTH exome

AF:

0.00296

GnomAD4 genome

AF:

0.0120

AC:

1823

AN:

152276

Hom.:

Cov.:

AF XY:

0.0112

AC XY:

834

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0412

Gnomad4 AMR

AF:

0.00373

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.00993

Alfa

AF:

0.00211

Hom.:

Bravo

AF:

0.0135

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0424

AC:

187

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00370

AC:

449

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

3 beta-Hydroxysteroid dehydrogenase deficiency

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 14, 2019	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 24, 2020	This variant is associated with the following publications: (PMID: 31611844, 9719627, 20981092, 10599696, 22995991, 11196452) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing;curation

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 14, 2020

Variant Summary: HSD3B2 c.707T>C (p.Leu236Ser) results in a non-conservative amino acid change located in the 3-beta hydroxysteroid dehydrogenase/isomerase domain (IPR002225) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.003 in 250862 control chromosomes, predominantly at a frequency of 0.042 within the African or African-American subpopulation in the gnomAD database, including 15 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 33 fold of the estimated maximal expected allele frequency for a pathogenic variant in HSD3B2 causing Congenital Adrenal Hyperplasia phenotype (0.0013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.707T>C has been reported in the literature in individuals affected with nonsalt wasting form of classical 3 beta HSD deficiency, hyperandrogenic adolescents, children with primary public hair and autoimmune Addison's disease patients (Nayak_1998, Moisan_1999, Aslaksen_2019). These reports however, do not provide unequivocal conclusions about association of the variant with Congenital Adrenal Hyperplasia. At least one publication reports experimental evidence evaluating an impact on protein function and the results showed no damaging effect of this variant on the kinetic properties and activity of 3 beta hydroxysteroid dehydrogenase enzyme (Moisan_1999). Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) or benign (n=1). Based on the evidence outlined above, the variant was re-classified as benign. -

HSD3B2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 02, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.33

T;T

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.0073

LIST_S2

Benign

0.35

T;.

MetaRNN

Benign

0.0068

T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

1.1

L;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

0.80

N;N

REVEL

Benign

0.18

Sift

Benign

0.23

T;T

Sift4G

Benign

0.23

T;T

Polyphen

0.016

B;B

Vest4

0.17

MVP

0.66

MPC

0.37

ClinPred

0.0040

GERP RS

-2.0

Varity_R

0.072

gMVP

0.40

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over