rs9332964

Positions:

chr2-31529325-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1PM2PP5_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:13O: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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_000348.4

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/exons	MANE
SRD5A2	NM_000348.4 linkuse as main transcript	c.680G>A	p.Arg227Gln	missense_variant	4/5	ENST00000622030.2
SRD5A2	XM_011533069.3 linkuse as main transcript	c.458G>A	p.Arg153Gln	missense_variant	4/5
SRD5A2	XM_011533072.3 linkuse as main transcript	c.425G>A	p.Arg142Gln	missense_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRD5A2	ENST00000622030.2 linkuse as main transcript	c.680G>A	p.Arg227Gln	missense_variant	4/5	1	NM_000348.4	P1
	ENST00000435713.1 linkuse as main transcript	n.255+1625C>T		intron_variant, non_coding_transcript_variant		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:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Pathogenic:9

Pathogenic, no assertion criteria provided	research	Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital	May 31, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Apr 12, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	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). -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Hue University of Medicine and Pharmacy	Nov 15, 2019	This variant, NM_000348.4:c.680G>A, was found in compound heterozygosity with the pathogenic variant NM_000348.4:c.485A>C. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	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 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 22, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	-	- -

not provided

Pathogenic:1Other:1

not provided, no classification provided	literature only	University of Sydney Medical Foundation	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 15, 2016	- -

SRD5A2-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 16, 2023

The SRD5A2 c.680G>A variant is predicted to result in the amino acid substitution p.Arg227Gln. This variant has been reported to be causative for steroid 5-alpha-reductase deficiency (OMIM #264600) in multiple affected individuals (Hiort et al. 1996. PubMed ID: 8784107; Kon et al. 2015. PubMed ID: 25605705; Nixon et al. 2017. PubMed ID: 28938747). This variant was reported to markedly reduce enzyme activity (Makridakis et al. 2000. PubMed ID: 10898110). This variant is reported in 0.67% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-31754395-C-T). This variant is interpreted as likely pathogenic. -

Micropenis

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2003

- -

Autism spectrum disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Gene Friend Way, National Innovation Center

Jul 28, 2023

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