rs121434247

Positions:

chr2-31531371-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong

The ENST00000622030.2(SRD5A2):c.547G>A(p.Gly183Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,575,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

SRD5A2
ENST00000622030.2 missense, splice_region

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.50

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 13 ACMG points.

PM1

In a chain 3-oxo-5-alpha-steroid 4-dehydrogenase 2 (size 253) in uniprot entity S5A2_HUMAN there are 57 pathogenic changes around while only 18 benign (76%) in ENST00000622030.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.796

PP5

Variant 2-31531371-C-T is Pathogenic according to our data. Variant chr2-31531371-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SRD5A2	NM_000348.4 linkuse as main transcript	c.547G>A	p.Gly183Ser	missense_variant, splice_region_variant	3/5	ENST00000622030.2	NP_000339.2
SRD5A2	XM_011533069.3 linkuse as main transcript	c.325G>A	p.Gly109Ser	missense_variant, splice_region_variant	3/5		XP_011531371.1
SRD5A2	XM_011533072.3 linkuse as main transcript	c.292G>A	p.Gly98Ser	missense_variant, splice_region_variant	5/7		XP_011531374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SRD5A2	ENST00000622030.2 linkuse as main transcript	c.547G>A	p.Gly183Ser	missense_variant, splice_region_variant	3/5	1	NM_000348.4	ENSP00000477587	P1
	ENST00000435713.1 linkuse as main transcript	n.255+3671C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000310

AC:

AN:

193796

Hom.:

AF XY:

0.0000388

AC XY:

AN XY:

103180

show subpopulations

Gnomad AFR exome

AF:

0.000436

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:

0.00

Gnomad OTH exome

AF:

0.000197

GnomAD4 exome

AF:

0.0000141

AC:

AN:

1422982

Hom.:

Cov.:

AF XY:

0.0000114

AC XY:

AN XY:

704272

show subpopulations

Gnomad4 AFR exome

AF:

0.000456

Gnomad4 AMR exome

AF:

0.0000256

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:

0.00

Gnomad4 OTH exome

AF:

0.0000678

GnomAD4 genome

AF:

0.000145

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.000458

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000326

Hom.:

Bravo

AF:

0.000181

ESP6500AA

AF:

0.000260

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000167

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Biochemistry Laboratory, Health Services Laboratory	Nov 20, 2023	ACMG:PS5 PM2 PM3 PP4 PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 183 of the SRD5A2 protein (p.Gly183Ser). This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon. This variant is present in population databases (rs121434247, gnomAD 0.04%). This missense change has been observed in individual(s) with steroid 5-alpha-reductase deficiency (PMID: 1522235, 18314109, 18350250, 28544750). ClinVar contains an entry for this variant (Variation ID: 3341). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects SRD5A2 function (PMID: 18350250). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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	Sep 23, 2013	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1996	- -

SRD5A2-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 28, 2024

The SRD5A2 c.547G>A variant is predicted to result in the amino acid substitution p.Gly183Ser. This variant has been reported in the homozygous and compound heterozygous state in multiple individuals with steroid 5-alpha-reductase deficiency (S5ARD) and has been reported in both sporadic cases and in individuals with a family history of S5ARD (Thigpen et al. 1992. PubMed ID: 1522235; Cai et al. 1996. PubMed ID: 8626825; Sahakitrungruang et al. 2008. PubMed ID: 18314109; Liu et al. 2022. PubMed ID: 35700942; Milewich et al. 1995. PubMed ID: 7593415; Hackel et al. 2005 PubMed ID 15770495; Table S5, Gomes et al. 2022. PubMed ID: 35134971). In vitro experimental studies show this variant affects the catalytic activity of the enzyme by decreasing its affinity for testosterone substrate, with a residual activity ~12% compared to control (Wigley et al. 1994. PubMed ID: 8110760; Vilchis et al. 2008. PubMed ID: 18350250). This variant is reported in ~0.050% of alleles in individuals of African descent in gnomAD, and has been described as a founder variant in individuals of Brazilian and Domican ancestry (Hackel et al. 2005 PMID 15770495). This variant has been classified as pathogenic by multiple clinical labs in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/3341/). Taken together, we classify this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.037

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Benign

0.96

FATHMM_MKL

Pathogenic

0.97

MetaRNN

Pathogenic

0.80

PrimateAI

Uncertain

0.56

Sift4G

Pathogenic

0.0

Vest4

0.94

MVP

0.56

GERP RS

5.5

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.87

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.87

Position offset: 0

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