rs1553329427

Positions:

• chr2-31580682-GA-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000348.4(SRD5A2):​c.218del​(p.Leu73ProfsTer58) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 35)
• Consequence: SRD5A2 NM_000348.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.730

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-31580682-GA-G is Pathogenic according to our data. Variant chr2-31580682-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 548143.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.218del	p.Leu73ProfsTer58	frameshift_variant	1/5	ENST00000622030.2
SRD5A2	XM_011533072.3	c.27-46917del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRD5A2	ENST00000622030.2	c.218del	p.Leu73ProfsTer58	frameshift_variant	1/5	1	NM_000348.4	P1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 35

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

research

Institute of Reproductive and Stem Cell Engineering, Central South University

Feb 01, 2018

The single-base deletion led to a frameshift mutation which was predicted to result in the formation of a truncated SRD5A2 protein with a stop codon at position 88. Although no functional studies have been performed, a mutant protein lacking several key regions could be pathogenic, be degraded, or confer a loss of function. This variant was detected in compound heterozygosity with NM_000348.3:c.680G>A in twin patients who presented with the same phenotype (perineal hypospadias, micropenis, and bilateral cryptorchidism) and were raised as females. -

Computational scores

Source: dbNSFP v4.3

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: rs1553329427; hg19: chr2-31805752;