rs121434252

chr2-31529370-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_000348.4(SRD5A2):c.635C>G(p.Pro212Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. P212P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: SRD5A2 NM_000348.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 9.92

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]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 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 NM_000348.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853
• PP5: Variant 2-31529370-G-C is Pathogenic according to our data. Variant chr2-31529370-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 3348.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRD5A2	NM_000348.4	c.635C>G	p.Pro212Arg	missense_variant	4/5	ENST00000622030.2
SRD5A2	XM_011533069.3	c.413C>G	p.Pro138Arg	missense_variant	4/5
SRD5A2	XM_011533072.3	c.380C>G	p.Pro127Arg	missense_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRD5A2	ENST00000622030.2	c.635C>G	p.Pro212Arg	missense_variant	4/5	1	NM_000348.4	P1
	ENST00000435713.1	n.255+1670G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000562 AC: 14 AN: 248918 Hom.: 0 AF XY: 0.0000666 AC XY: 9 AN XY: 135042

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000406

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: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461634 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727084

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000358

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: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ExAC AF: 0.0000662 AC: 8

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2000	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Mar 17, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 14, 2024	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 212 of the SRD5A2 protein (p.Pro212Arg). This variant is present in population databases (rs121434252, gnomAD 0.04%). This missense change has been observed in individuals with disorders of sex development (PMID: 8110760, 8262007, 9135696, 10718838, 10999800, 20019388). It is commonly reported in individuals of Mexican ancestry (PMID: 8110760, 8262007, 9135696, 10718838, 10999800, 20019388). ClinVar contains an entry for this variant (Variation ID: 3348). 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 expected to disrupt SRD5A2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SRD5A2 function (PMID: 8110760, 24665940). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Uncertain	0.11
Cadd	Pathogenic	29
Dann	Benign	0.73
FATHMM_MKL	Uncertain	0.95	D
MetaRNN	Pathogenic	0.85	D
PrimateAI	Uncertain	0.55	T
Sift4G	Uncertain	0.026	D
Vest4		0.97
MVP		0.57
GERP RS		5.7
gMVP		0.97

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

Other links and lift over

dbSNP: rs121434252; hg19: chr2-31754440;