rs9332964

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The NM_000348.4(SRD5A2):c.680G>A(p.Arg227Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000112 in 1,613,804 control chromosomes in the GnomAD database, including 1 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00022 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

SRD5A2
NM_000348.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 4.99

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:

ENSG00000228563 (HGNC:):

ENSG00000228563 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-31529325-C-T is Pathogenic according to our data. Variant chr2-31529325-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-31529325-C-T is described in Lovd as [Pathogenic]. Variant chr2-31529325-C-T is described in Lovd as [Likely_benign].

BP4

Computational evidence support a benign effect (MetaRNN=0.016074628). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRD5A2	NM_000348.4 link	c.680G>A	p.Arg227Gln	missense_variant	Exon 4 of 5	ENST00000622030.2	NP_000339.2	P31213
SRD5A2	XM_011533069.3 link	c.458G>A	p.Arg153Gln	missense_variant	Exon 4 of 5		XP_011531371.1
SRD5A2	XM_011533072.3 link	c.425G>A	p.Arg142Gln	missense_variant	Exon 6 of 7		XP_011531374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRD5A2	ENST00000622030.2 link	c.680G>A	p.Arg227Gln	missense_variant	Exon 4 of 5	1	NM_000348.4	ENSP00000477587.1		P31213
ENSG00000228563	ENST00000435713.1 link	n.255+1625C>T		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.000223

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00655

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000474

AC:

118

AN:

248938

Hom.:

AF XY:

0.000452

AC XY:

AN XY:

135048

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00652

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000999

AC:

146

AN:

1461554

Hom.:

Cov.:

AF XY:

0.0000990

AC XY:

AN XY:

727042

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00323

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000223

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00656

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000133

Hom.:

Bravo

AF:

0.000227

ExAC

AF:

0.000422

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Pathogenic:11

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency (MONDO:0009923). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (32 heterozygotes, 1 homozygote). (SP) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0600 - Variant is located in the annotated 3-oxo-5-alpha-steroid 4-dehydrogenase domain (NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in multiple East Asian patients with 5α-reductase 2 deficiency (ClinVar, PMID: 32713132). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies show that this variant causes reduced enzyme activity (PMID: 10898110). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Apr 12, 2016

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

NM_000348.3:c.680G>A in the SRD5A2 gene has an allele frequency of 0.006 in East Asian subpopulation in the gnomAD database. Cheng J et al. reported that the c.680G>A (p.Arg227Gln) mutation was identified in 16 homozygous patients, 17 compound heterozygous patients, eight heterozygous patients with 5-alpha-reductase type 2 deficiency (PMID: 25899528 ). Experimental studies have shown that this missense change reduces enzyme activity (PMID: 10898110). In addition, Cancio et al. reported a male pseudohermaphrodite patient harboring R227Q with a frameshift mutation from codon 219. These two variants were located in a different allele (PMID: 15064320). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PS3, PM3_Strong, PP4. -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as a Likely Pathogenic, for Pseudovaginal perineoscrotal hypospadias, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PS3 => Well-established functional studies show a deleterious effect (PMID:10898110). PM2-Supporting => PM2 downgraded in strength to Supporting. PS4-Supporting => PS4 downgraded in strength to Supporting. Recurrently seen in non-related affected individuals (PMID:25899528). PM3-Supporting => PM3 downgraded in strength to Supporting (PMID:15064320). -

Apr 24, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 227 of the SRD5A2 protein (p.Arg227Gln). This variant is present in population databases (rs9332964, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with steroid 5-alpha-reductase deficiency (PMID: 12843198, 14594182, 19342739, 20736251, 22453073, 25605705, 25899528). It is commonly reported in individuals of East Asian ancestry (PMID: 12843198, 14594182, 19342739, 20736251, 22453073, 25605705, 25899528). ClinVar contains an entry for this variant (Variation ID: 3351). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SRD5A2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SRD5A2 function (PMID: 10898110). For these reasons, this variant has been classified as Pathogenic. -

Nov 15, 2019

Department of Medical Genetics, Hue University of Medicine and Pharmacy

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, NM_000348.4:c.680G>A, was found in compound heterozygosity with the pathogenic variant NM_000348.4:c.485A>C. -

Sep 14, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.047%). Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 10898110). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003351 /PMID: 8784107). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 10898110). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 22, 2017

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 31, 2019

Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided

Pathogenic:1Other:1

University of Sydney Medical Foundation

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Apr 15, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SRD5A2-related disorder

Pathogenic:1

May 20, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SRD5A2 c.680G>A variant is predicted to result in the amino acid substitution p.Arg227Gln. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with steroid 5-alpha-reductase deficiency (see for example, Table 2, Hiort et al. 1996. PubMed ID: 8784107; Table 1, Kon et al. 2015. PubMed ID: 25605705; Table 2, Zhang et al. 2019. PubMed ID: 31219235). This variant is reported in 0.67% of alleles in individuals of East Asian descent in gnomAD. An in vitro experimental study has shown this variant markedly reduces enzyme activity (Table 2, Makridakis et al. 2000. PubMed ID: 10898110). This variant is interpreted as likely pathogenic. -

Micropenis

Pathogenic:1

Jul 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Autism spectrum disorder

Pathogenic:1

Jul 28, 2023

Gene Friend Way, National Innovation Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

A nonsynonymous change known as R227Q in the SRD5A2 gene. The SRD5A2 gene encodes steroid 5-alpha-reductase, an enzyme which catalyzes the conversion of testosterone in the body. Some research shows that there is a role for the adrenal glands in ASD (PMID: 34493761). Variants of SRD5A2 related to autism/ autistic-like traits have been reported (PMID: 35042285, 23867117). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.23

CADD

Pathogenic

DANN

Benign

0.91

FATHMM_MKL

Uncertain

0.88

MetaRNN

Benign

0.016

PrimateAI

Benign

0.30

Sift4G

Uncertain

0.044

Vest4

0.76

MVP

0.53

GERP RS

4.6

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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