rs9282858

Variant names:

• chr2-31580756-C-T
• rs9282858
• NM_000348.4:c.145G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000348.4(SRD5A2):​c.145G>A​(p.Ala49Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0298 in 1,610,538 control chromosomes in the GnomAD database, including 914 homozygotes. In-silico tool predicts a benign outcome for this variant. 7/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (43 hom., cov: 35)
  • Exomes 𝑓: 0.031 (871 hom.)
• Consequence: SRD5A2 NM_000348.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 U:1 B:5 O:1
• Conservation: PhyloP100: 2.90

Genes affected

SRD5A2 (HGNC:11285): (steroid 5 alpha-reductase 2) This gene encodes a microsomal protein expressed at high levels in androgen-sensitive tissues such as the prostate. The encoded protein is active at acidic pH and is sensitive to the 4-azasteroid inhibitor finasteride. Deficiencies in this gene can result in male pseudohermaphroditism, specifically pseudovaginal perineoscrotal hypospadias (PPSH). [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0075003505).
• BP6: Variant 2-31580756-C-T is Benign according to our data. Variant chr2-31580756-C-T is described in ClinVar as [Benign]. Clinvar id is 3347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0202 (3075/152376) while in subpopulation NFE AF= 0.0324 (2202/68032). AF 95% confidence interval is 0.0312. There are 43 homozygotes in gnomad4. There are 1438 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 43 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRD5A2	NM_000348.4	c.145G>A	p.Ala49Thr	missense_variant	Exon 1 of 5	ENST00000622030.2	NP_000339.2
SRD5A2	XM_011533072.3	c.27-46990G>A		intron_variant	Intron 3 of 6		XP_011531374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRD5A2	ENST00000622030.2	c.145G>A	p.Ala49Thr	missense_variant	Exon 1 of 5	1	NM_000348.4	ENSP00000477587.1

Frequencies

GnomAD3 genomes AF: 0.0202 AC: 3075 AN: 152258 Hom.: 43 Cov.: 35

Gnomad AFR AF: 0.00718

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0163

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0324

Gnomad OTH AF: 0.0201

GnomAD3 exomes AF: 0.0175 AC: 4187 AN: 238830 Hom.: 61 AF XY: 0.0176 AC XY: 2315 AN XY: 131350

Gnomad AFR exome AF: 0.00671

Gnomad AMR exome AF: 0.0122

Gnomad ASJ exome AF: 0.00691

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00249

Gnomad FIN exome AF: 0.0208

Gnomad NFE exome AF: 0.0280

Gnomad OTH exome AF: 0.0197

GnomAD4 exome AF: 0.0308 AC: 44852 AN: 1458162 Hom.: 871 Cov.: 38 AF XY: 0.0299 AC XY: 21682 AN XY: 725582

Gnomad4 AFR exome AF: 0.00517

Gnomad4 AMR exome AF: 0.0132

Gnomad4 ASJ exome AF: 0.00644

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00242

Gnomad4 FIN exome AF: 0.0209

Gnomad4 NFE exome AF: 0.0369

Gnomad4 OTH exome AF: 0.0267

GnomAD4 genome AF: 0.0202 AC: 3075 AN: 152376 Hom.: 43 Cov.: 35 AF XY: 0.0193 AC XY: 1438 AN XY: 74516

Gnomad4 AFR AF: 0.00716

Gnomad4 AMR AF: 0.0163

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0198

Gnomad4 NFE AF: 0.0324

Gnomad4 OTH AF: 0.0198

Alfa AF: 0.0302 Hom.: 140

Bravo AF: 0.0199

ESP6500AA AF: 0.00606 AC: 23

ESP6500EA AF: 0.0306 AC: 251

ExAC AF: 0.0162 AC: 1945

Asia WGS AF: 0.00115 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Uncertain:1 Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency Pathogenic:1 Benign:2

May 23, 2011

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

European Non-Finnish population allele frequency is 3.124%% (rs9282858, 3075/152258 alleles, 43 homozygotes in gnomAD v3.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as BENIGN. Following criteria are met: BA1 -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2 Other:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

University of Sydney Medical Foundation

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 31942420) -

SRD5A2-related disorder Uncertain:1

Aug 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SRD5A2 c.145G>A variant is predicted to result in the amino acid substitution p.Ala49Thr. This variant has been reported in association with an increased risk of mild hypospadias (Rahimi et al. 2017. PubMed ID: 27848231; Silver and Russell. 1999. PubMed ID: 10458450; Thai et al. 2005. PubMed ID: 16174723). However, this variant is also reported in 2.8% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

SRD5A2 POLYMORPHISM Benign:1

Aug 15, 2008

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	20
DANN	Benign	0.80
FATHMM_MKL	Uncertain	0.86	D
MetaRNN	Benign	0.0075	T
PrimateAI	Uncertain	0.50	T
Sift4G	Uncertain	0.0050	D
Vest4		0.82
GERP RS		3.4
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs9282858; hg19: chr2-31805826;