rs9282858

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBS1BS2

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 (★★). Synonymous variant affecting the same amino acid position (i.e. A49A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.020 ( 43 hom., cov: 35)

Exomes 𝑓: 0.031 ( 871 hom. )

Consequence

SRD5A2
NM_000348.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1U:1B:5O:1

Conservation

PhyloP100: 2.90

Publications

114 publications found

Variant links:

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]

SRD5A2 Gene-Disease associations (from GenCC):

46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

SRD5A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000348.4

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 40 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Trascript score misZ: -0.88748 (below the threshold of 3.09). GenCC associations: The gene is linked to 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency.

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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 43 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000348.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRD5A2	NM_000348.4	MANE Select	c.145G>A	p.Ala49Thr	missense	Exon 1 of 5	NP_000339.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRD5A2	ENST00000622030.2	TSL:1 MANE Select	c.145G>A	p.Ala49Thr	missense	Exon 1 of 5	ENSP00000477587.1

Frequencies

GnomAD3 genomes

AF:

0.0202

AC:

3075

AN:

152258

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0175

AC:

4187

AN:

238830

AF XY:

0.0176

show subpopulations

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 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.:

AF XY:

0.0299

AC XY:

21682

AN XY:

725582

show subpopulations

African (AFR)

AF:

0.00517

AC:

173

AN:

33460

American (AMR)

AF:

0.0132

AC:

589

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.00644

AC:

168

AN:

26092

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00242

AC:

209

AN:

86210

European-Finnish (FIN)

AF:

0.0209

AC:

1056

AN:

50548

Middle Eastern (MID)

AF:

0.00210

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.0369

AC:

41038

AN:

1111542

Other (OTH)

AF:

0.0267

AC:

1607

AN:

60238

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

2977

5954

8932

11909

14886

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1540

3080

4620

6160

7700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0202

AC:

3075

AN:

152376

Hom.:

Cov.:

AF XY:

0.0193

AC XY:

1438

AN XY:

74516

show subpopulations

African (AFR)

AF:

0.00716

AC:

298

AN:

41598

American (AMR)

AF:

0.0163

AC:

250

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.00145

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0198

AC:

211

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0324

AC:

2202

AN:

68032

Other (OTH)

AF:

0.0198

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

166

333

499

666

832

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0289

Hom.:

189

Bravo

AF:

0.0199

ESP6500AA

AF:

0.00606

AC:

ESP6500EA

AF:

0.0306

AC:

251

ExAC

AF:

0.0162

AC:

1945

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign

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

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency

Pathogenic:1Benign:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

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

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

not provided

Benign:2Other:1

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)

University of Sydney Medical Foundation

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.80

FATHMM_MKL

Uncertain

0.86

MetaRNN

Benign

0.0075

PhyloP100

2.9

PrimateAI

Uncertain

0.50

Sift4G

Uncertain

0.0050

Vest4

0.82

GERP RS

3.4

PromoterAI

-0.0096

Neutral

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over