rs121434251

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong

The NM_000348.4(SRD5A2):c.692A>G(p.His231Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000285 in 1,613,614 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H231Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00030 ( 0 hom. )

Consequence

SRD5A2
NM_000348.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 7.96

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 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, 3 uncertain in NM_000348.4

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-31529313-T-C is Pathogenic according to our data. Variant chr2-31529313-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 3346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-31529313-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SRD5A2	NM_000348.4 linkuse as main transcript	c.692A>G	p.His231Arg	missense_variant	4/5	ENST00000622030.2
SRD5A2	XM_011533069.3 linkuse as main transcript	c.470A>G	p.His157Arg	missense_variant	4/5
SRD5A2	XM_011533072.3 linkuse as main transcript	c.437A>G	p.His146Arg	missense_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRD5A2	ENST00000622030.2 linkuse as main transcript	c.692A>G	p.His231Arg	missense_variant	4/5	1	NM_000348.4	P1
	ENST00000435713.1 linkuse as main transcript	n.255+1613T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000153

AC:

AN:

248940

Hom.:

AF XY:

0.000133

AC XY:

AN XY:

135048

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000328

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000298

AC:

436

AN:

1461528

Hom.:

Cov.:

AF XY:

0.000298

AC XY:

217

AN XY:

727036

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000384

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000158

AC:

AN:

152086

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000725

Hom.:

Bravo

AF:

0.000155

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000488

AC:

ExAC

AF:

0.000157

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 01, 2022	DNA sequence analysis of the SRD5A2 gene demonstrated two sequence changes. The first sequence change, c.692A>G, is located in exon 4 and results in an amino acid change, p.His231Arg. The p.His231Arg change affects a highly conserved amino acid residue located in a domain of the SRD5A2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.His231Arg substitution. This pathogenic sequence change has previously been described in individuals with SRD5A2-related disorders in the homozygous or compound heterozygous state (PMID: 27899157, 8706317, 9745434, 1522235). This sequence change has been described in the gnomAD database with a frequency of 0.03% in the European subpopulation (dbSNP rs121434251). These collective evidences indicate that this sequence change is pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2020	Published functional studie demonstrates reduced testosterone binding (Wigley et al., 1994); Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28544750, 28110336, 1522235, 7608269, 10458450, 9745434, 8784107, 8110760, 21402750) -

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

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 231 of the SRD5A2 protein (p.His231Arg). This variant is present in population databases (rs121434251, gnomAD 0.03%). This missense change has been observed in individual(s) with 5 alpha-reductase 2 deficiency (PMID: 1522235, 7608269, 8706317, 8723114, 9745434, 27899157, 28544750). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3346). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SRD5A2 protein function. Experimental studies have shown that this missense change affects SRD5A2 function (8110760.1522235). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Jun 12, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 1998	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Uncertain

0.014

BayesDel_noAF

Uncertain

0.090

Cadd

Uncertain

Dann

Benign

0.87

FATHMM_MKL

Uncertain

0.94

MetaRNN

Uncertain

0.66

PrimateAI

Uncertain

0.61

Sift4G

Pathogenic

0.0

Vest4

0.73

MVP

0.57

GERP RS

5.5

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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