NM_000348.4:c.586G>A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_000348.4(SRD5A2):c.586G>A(p.Gly196Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000793 in 1,613,802 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000073 ( 1 hom. )

Consequence

SRD5A2
NM_000348.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.84

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 Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.836

PP5

Variant 2-31529419-C-T is Pathogenic according to our data. Variant chr2-31529419-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRD5A2	NM_000348.4 link	c.586G>A	p.Gly196Ser	missense_variant	Exon 4 of 5	ENST00000622030.2	NP_000339.2	P31213
SRD5A2	XM_011533069.3 link	c.364G>A	p.Gly122Ser	missense_variant	Exon 4 of 5		XP_011531371.1
SRD5A2	XM_011533072.3 link	c.331G>A	p.Gly111Ser	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.586G>A	p.Gly196Ser	missense_variant	Exon 4 of 5	1	NM_000348.4	ENSP00000477587.1		P31213
ENSG00000228563	ENST00000435713.1 link	n.255+1719C>T		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000137

AC:

AN:

248732

Hom.:

AF XY:

0.000104

AC XY:

AN XY:

134946

show subpopulations

Gnomad AFR exome

AF:

0.000323

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000167

Gnomad SAS exome

AF:

0.000262

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000151

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000725

AC:

106

AN:

1461526

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

727038

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000360

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000477

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.000144

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000153

Hom.:

Bravo

AF:

0.000155

ESP6500AA

AF:

0.00103

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000223

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Pathogenic:7

Feb 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 196 of the SRD5A2 protein (p.Gly196Ser). This variant is present in population databases (rs121434250, gnomAD 0.03%). This missense change has been observed in individual(s) with steroid 5-alpha-reductase deficiency (PMID: 18391525, 21147889, 21402750). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3345). 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: 1522235). For these reasons, this variant has been classified as Pathogenic. -

Apr 19, 2011

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 06, 2021

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 pseudovaginal perineoscrotal hypospadias (MIM#264600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (37 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and very high conservation. (I) 0600 - Variant is located in the annotated steroid dehydrogenase domain (NCBI, PDB). (I) 0702 – Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Residue 196 is considered to be a hotspot, with alternative changes to aspartic acid and arginine previously reported in individuals with pseudovaginal perineoscrotal hypospadias (MIM#264600) (ClinVar, PMIDs: 21402750, 28663096, 32346305). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported, in either a homozygous or compound heterozygous state, in multiple individuals with pseudovaginal perineoscrotal hypospadias (MIM#264600) (ClinVar, HGMD, PMIDs: 1522235, 25248670, 28110336). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. The variant has been shown the result in decreased enzyme activity and a reduced affinity for NADPH (PMID: 1522235). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Nov 20, 2023

Clinical Biochemistry Laboratory, Health Services Laboratory

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG:PS5 PM2 PM3 PP4 PP5 -

Dec 03, 2024

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

SRD5A2-related disorder

Pathogenic:1

Sep 20, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SRD5A2 c.586G>A variant is predicted to result in the amino acid substitution p.Gly196Ser. This variant has been reported in the homozygous and compound heterozygous state in several individuals with steroid 5-alpha-reductase deficiency (see, for example, Thigpen et al. 1992. PubMed ID: 1522235; Table 3, Akcay et al. 2014. PubMed ID: 24737579; Abacı et al. 2018. PubMed ID: 30132287) and was found to segregate with a second pathogenic variant in a family with 5-alpha-reductase deficiency (Nordenskjöld and Ivarsson. 1998. PubMed ID: 9745434). In vitro functional studies using HEK 293 cells show reduced affinity to NADPH and an increase in optimal pH; however, it does not seem to have an effect on testosterone activity (Thigpen et al. 1992. PubMed ID: 1522235). This variant is predicted to alter splicing based on available splicing prediction programs (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). An alternate nucleotide change affecting the same amino acid (c.587G>T; p.Gly196Val) has been reported in individuals with 5-alpha-reductase deficiency (Cheng et al. 2019. PubMed ID: 31031332; Liu et al. 2022. PubMed ID: 35700942). This variant is reported in 0.029% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Jan 31, 2020

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Uncertain

0.099

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Benign

0.79

FATHMM_MKL

Uncertain

0.93

MetaRNN

Pathogenic

0.84

PrimateAI

Uncertain

0.63

Sift4G

Uncertain

0.047

Vest4

0.87

MVP

0.54

GERP RS

5.6

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

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