rs9282858

Positions:

chr2-31580756-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_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 (★★).

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons	MANE	Protein	UniProt
SRD5A2	NM_000348.4 link	c.145G>A	p.Ala49Thr	missense_variant	1/5	ENST00000622030.2	NP_000339.2	P31213
SRD5A2	XM_011533072.3 link	c.27-46990G>A		intron_variant			XP_011531374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SRD5A2	ENST00000622030.2 link	c.145G>A	p.Ala49Thr	missense_variant	1/5	1	NM_000348.4	ENSP00000477587.1		P31213

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

GnomAD3 exomes

AF:

0.0175

AC:

4187

AN:

238830

Hom.:

AF XY:

0.0176

AC XY:

2315

AN XY:

131350

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 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.:

AF XY:

0.0299

AC XY:

21682

AN XY:

725582

show subpopulations

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.:

Cov.:

AF XY:

0.0193

AC XY:

1438

AN XY:

74516

show subpopulations

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:

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	May 23, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	May 04, 2023	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 -

not provided

Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 31942420) -
not provided, no classification provided	literature only	University of Sydney Medical Foundation	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

SRD5A2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 06, 2024

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

Benign, no assertion criteria provided

literature only

OMIM

Aug 15, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.80

FATHMM_MKL

Uncertain

0.86

MetaRNN

Benign

0.0075

PrimateAI

Uncertain

0.50

Sift4G

Uncertain

0.0050

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

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