rs28383048

chr2-31533711-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS2

The NM_000348.4(SRD5A2):c.337C>G(p.Leu113Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000341 in 1,597,022 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: SRD5A2 NM_000348.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.518

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 Benign. Variant got -7 ACMG points.

• PM1: In a helix (size 23) in uniprot entity S5A2_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_000348.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.013136238).
• BP6: Variant 2-31533711-G-C is Benign according to our data. Variant chr2-31533711-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 459636.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRD5A2	NM_000348.4	c.337C>G	p.Leu113Val	missense_variant	2/5	ENST00000622030.2
SRD5A2	XM_011533069.3	c.115C>G	p.Leu39Val	missense_variant	2/5
SRD5A2	XM_011533072.3	c.82C>G	p.Leu28Val	missense_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRD5A2	ENST00000622030.2	c.337C>G	p.Leu113Val	missense_variant	2/5	1	NM_000348.4	P1
	ENST00000435713.1	n.255+6011G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00178 AC: 271 AN: 152206 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00632

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.0000294

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000420 AC: 94 AN: 223596 Hom.: 0 AF XY: 0.000317 AC XY: 38 AN XY: 119972

Gnomad AFR exome AF: 0.00643

Gnomad AMR exome AF: 0.0000941

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000377

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000300

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000190 AC: 274 AN: 1444698 Hom.: 1 Cov.: 31 AF XY: 0.000179 AC XY: 128 AN XY: 716572

Gnomad4 AFR exome AF: 0.00623

Gnomad4 AMR exome AF: 0.000188

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000121

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000816

Gnomad4 OTH exome AF: 0.000718

GnomAD4 genome AF: 0.00178 AC: 271 AN: 152324 Hom.: 2 Cov.: 32 AF XY: 0.00158 AC XY: 118 AN XY: 74490

Gnomad4 AFR AF: 0.00630

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000254 Hom.: 1

Bravo AF: 0.00165

ESP6500AA AF: 0.00593 AC: 23

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000530 AC: 64

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 08, 2021

Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30238986, 22371315, 10458450, 21037542) -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 16, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	0.013
Dann	Benign	0.56
FATHMM_MKL	Benign	0.024	N
MetaRNN	Benign	0.013	T
PrimateAI	Benign	0.32	T
Sift4G	Benign	0.46	T
Vest4		0.70
MVP		0.29
GERP RS		-3.8
gMVP		0.39

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: rs28383048; hg19: chr2-31758781;