rs4986954

chr1-119419495-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000198.4(HSD3B2):c.220G>A(p.Asp74Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000617 in 1,613,814 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. D74D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0035 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (1 hom.)
• Consequence: HSD3B2 NM_000198.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 6.64

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010008693).
• BP6: Variant 1-119419495-G-A is Benign according to our data. Variant chr1-119419495-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 720898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSD3B2	NM_000198.4	c.220G>A	p.Asp74Asn	missense_variant	3/4	ENST00000369416.4
HSD3B2	NM_001166120.2	c.220G>A	p.Asp74Asn	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSD3B2	ENST00000369416.4	c.220G>A	p.Asp74Asn	missense_variant	3/4	1	NM_000198.4	P1

Frequencies

GnomAD3 genomes AF: 0.00352 AC: 536 AN: 152170 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000793 AC: 199 AN: 250902 Hom.: 0 AF XY: 0.000568 AC XY: 77 AN XY: 135592

Gnomad AFR exome AF: 0.0110

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000314 AC: 459 AN: 1461526 Hom.: 1 Cov.: 31 AF XY: 0.000268 AC XY: 195 AN XY: 727084

Gnomad4 AFR exome AF: 0.0112

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.000795

GnomAD4 genome AF: 0.00352 AC: 536 AN: 152288 Hom.: 7 Cov.: 32 AF XY: 0.00344 AC XY: 256 AN XY: 74464

Gnomad4 AFR AF: 0.0125

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00169 Hom.: 0

Bravo AF: 0.00359

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00885 AC: 39

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00106 AC: 129

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2020	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

3 beta-Hydroxysteroid dehydrogenase deficiency Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.34
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T;T
Eigen	Benign	-0.0023
Eigen_PC	Benign	0.018
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D;.
MetaRNN	Benign	0.010	T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.0	L;.;L
MutationTaster	Benign	0.77	N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.52	N;N;N
REVEL	Uncertain	0.38
Sift	Uncertain	0.010	D;D;D
Sift4G	Uncertain	0.043	D;D;D
Polyphen		0.46	P;.;P
Vest4		0.22
MVP		0.91
MPC		0.36
ClinPred		0.083	T
GERP RS		3.9
Varity_R		0.22
gMVP		0.11

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

Other links and lift over

dbSNP: rs4986954; hg19: chr1-119962118;