rs121434247

chr2-31531371-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000348.4(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 NM_000348.4 missense, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.50

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 Pathogenic. Variant got 14 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: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• 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	UniProt
SRD5A2	NM_000348.4	c.547G>A	p.Gly183Ser	missense_variant, splice_region_variant	3/5	ENST00000622030.2
SRD5A2	XM_011533069.3	c.325G>A	p.Gly109Ser	missense_variant, splice_region_variant	3/5
SRD5A2	XM_011533072.3	c.292G>A	p.Gly98Ser	missense_variant, splice_region_variant	5/7

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152168 Hom.: 0 Cov.: 32

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: 6 AN: 193796 Hom.: 0 AF XY: 0.0000388 AC XY: 4 AN XY: 103180

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: 20 AN: 1422982 Hom.: 0 Cov.: 29 AF XY: 0.0000114 AC XY: 8 AN XY: 704272

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: 22 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74326

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.: 0

Bravo AF: 0.000181

ESP6500AA AF: 0.000260 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000167 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1996	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Biochemistry Laboratory, Health Services Laboratory	Nov 20, 2023	ACMG:PS5 PM2 PM3 PP4 PP5 -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Sep 23, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Uncertain	0.060
Cadd	Pathogenic	34
Dann	Benign	0.96
FATHMM_MKL	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.80	D
PrimateAI	Uncertain	0.56	T
Sift4G	Pathogenic	0.0	D
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

Other links and lift over

dbSNP: rs121434247; hg19: chr2-31756441;