rs9282858

chr2-31580756-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000348.4(SRD5A2):c.145G>A(p.Ala49Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0298 in 1,610,538 control chromosomes in the GnomAD database, including 914 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A49A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.020 (43 hom., cov: 35)
  • Exomes 𝑓: 0.031 (871 hom.)
• Consequence: SRD5A2 NM_000348.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:4 O:1
• Conservation: PhyloP100: 2.90

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000348.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0075003505).
• BP6: Variant 2-31580756-C-T is Benign according to our data. Variant chr2-31580756-C-T is described in ClinVar as [Benign]. Clinvar id is 3347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0202 (3075/152376) while in subpopulation NFE AF= 0.0324 (2202/68032). AF 95% confidence interval is 0.0312. There are 43 homozygotes in gnomad4. There are 1438 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 43 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRD5A2	NM_000348.4	c.145G>A	p.Ala49Thr	missense_variant	1/5	ENST00000622030.2
SRD5A2	XM_011533072.3	c.27-46990G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRD5A2	ENST00000622030.2	c.145G>A	p.Ala49Thr	missense_variant	1/5	1	NM_000348.4	P1

Frequencies

GnomAD3 genomes AF: 0.0202 AC: 3075 AN: 152258 Hom.: 43 Cov.: 35

Gnomad AFR AF: 0.00718

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0163

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0324

Gnomad OTH AF: 0.0201

GnomAD3 exomes AF: 0.0175 AC: 4187 AN: 238830 Hom.: 61 AF XY: 0.0176 AC XY: 2315 AN XY: 131350

Gnomad AFR exome AF: 0.00671

Gnomad AMR exome AF: 0.0122

Gnomad ASJ exome AF: 0.00691

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00249

Gnomad FIN exome AF: 0.0208

Gnomad NFE exome AF: 0.0280

Gnomad OTH exome AF: 0.0197

GnomAD4 exome AF: 0.0308 AC: 44852 AN: 1458162 Hom.: 871 Cov.: 38 AF XY: 0.0299 AC XY: 21682 AN XY: 725582

Gnomad4 AFR exome AF: 0.00517

Gnomad4 AMR exome AF: 0.0132

Gnomad4 ASJ exome AF: 0.00644

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00242

Gnomad4 FIN exome AF: 0.0209

Gnomad4 NFE exome AF: 0.0369

Gnomad4 OTH exome AF: 0.0267

GnomAD4 genome AF: 0.0202 AC: 3075 AN: 152376 Hom.: 43 Cov.: 35 AF XY: 0.0193 AC XY: 1438 AN XY: 74516

Gnomad4 AFR AF: 0.00716

Gnomad4 AMR AF: 0.0163

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0198

Gnomad4 NFE AF: 0.0324

Gnomad4 OTH AF: 0.0198

Alfa AF: 0.0302 Hom.: 140

Bravo AF: 0.0199

ESP6500AA AF: 0.00606 AC: 23

ESP6500EA AF: 0.0306 AC: 251

ExAC AF: 0.0162 AC: 1945

Asia WGS AF: 0.00115 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency Pathogenic:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	May 04, 2023	European Non-Finnish population allele frequency is 3.124%% (rs9282858, 3075/152258 alleles, 43 homozygotes in gnomAD v3.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as BENIGN. Following criteria are met: BA1 -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	May 23, 2011	- -

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 31942420) -
not provided, no classification provided	literature only	University of Sydney Medical Foundation	-	- -

STEROID 5-ALPHA-REDUCTASE POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Aug 15, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	20
Dann	Benign	0.80
FATHMM_MKL	Uncertain	0.86	D
MetaRNN	Benign	0.0075	T
PrimateAI	Uncertain	0.50	T
Sift4G	Uncertain	0.0050	D
Vest4		0.82
GERP RS		3.4
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs9282858; hg19: chr2-31805826;