Genetic Variant HSD3B1:p.Arg71Ile (chr1-119511569-G-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_000862.3(HSD3B1):c.212G>T(p.Arg71Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00679 in 1,613,798 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0046 ( 3 hom., cov: 31)

Exomes 𝑓: 0.0070 ( 39 hom. )

Consequence

HSD3B1
NM_000862.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0340

Variant links:

Genes affected

HSD3B1 (HGNC:5217): (hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1) The protein encoded by this gene is an enzyme that catalyzes the oxidative conversion of delta-5-3-beta-hydroxysteroid precursors into delta-4-ketosteroids, which leads to the production of all classes of steroid hormones. The encoded protein also catalyzes the interconversion of 3-beta-hydroxy- and 3-keto-5-alpha-androstane steroids. [provided by RefSeq, Jun 2016]

HSD3B1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014194846).

BP6

Variant 1-119511569-G-T is Benign according to our data. Variant chr1-119511569-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 3387985.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD3B1	NM_000862.3 link	c.212G>T	p.Arg71Ile	missense_variant	Exon 3 of 4	ENST00000369413.8	NP_000853.1	P14060
HSD3B1	NM_001328615.1 link	c.212G>T	p.Arg71Ile	missense_variant	Exon 3 of 4		NP_001315544.1	P14060

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HSD3B1	ENST00000369413.8 link	c.212G>T	p.Arg71Ile	missense_variant	Exon 3 of 4	1	NM_000862.3	ENSP00000358421.3	P14060
HSD3B1	ENST00000528909.1 link	c.212G>T	p.Arg71Ile	missense_variant	Exon 2 of 3	1		ENSP00000432268.1	P14060
HSD3B1	ENST00000531340.5 link	c.212G>T	p.Arg71Ile	missense_variant	Exon 3 of 3	3		ENSP00000435999.1	E9PRN7
HSD3B1	ENST00000492140.1 link	n.347G>T		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.00464

AC:

706

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00140

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00438

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00208

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00794

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00409

AC:

1025

AN:

250902

Hom.:

AF XY:

0.00422

AC XY:

572

AN XY:

135584

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.00229

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00170

Gnomad FIN exome

AF:

0.00129

Gnomad NFE exome

AF:

0.00716

Gnomad OTH exome

AF:

0.00310

GnomAD4 exome

AF:

0.00702

AC:

10257

AN:

1461534

Hom.:

Cov.:

AF XY:

0.00685

AC XY:

4978

AN XY:

727084

show subpopulations

Gnomad4 AFR exome

AF:

0.00102

Gnomad4 AMR exome

AF:

0.00244

Gnomad4 ASJ exome

AF:

0.00115

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00160

Gnomad4 FIN exome

AF:

0.00159

Gnomad4 NFE exome

AF:

0.00855

Gnomad4 OTH exome

AF:

0.00578

GnomAD4 genome

AF:

0.00464

AC:

706

AN:

152264

Hom.:

Cov.:

AF XY:

0.00428

AC XY:

319

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00140

Gnomad4 AMR

AF:

0.00438

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00208

Gnomad4 FIN

AF:

0.00141

Gnomad4 NFE

AF:

0.00794

Gnomad4 OTH

AF:

0.00427

Alfa

AF:

0.00545

Hom.:

Bravo

AF:

0.00436

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00882

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00849

AC:

ExAC

AF:

0.00393

AC:

477

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00714

EpiControl

AF:

0.00711

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HSD3B1: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.62

D;D;D

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.12

LIST_S2

Uncertain

0.91

D;.;D

MetaRNN

Benign

0.014

T;T;T

MetaSVM

Uncertain

0.21

MutationAssessor

Pathogenic

3.5

.;M;M

PrimateAI

Benign

0.28

PROVEAN

Pathogenic

-5.9

D;D;D

REVEL

Uncertain

0.41

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

0.93

.;P;P

Vest4

0.56

MVP

0.92

MPC

0.16

ClinPred

0.091

GERP RS

0.84

Varity_R

0.38

gMVP

0.20

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