2-31525043-TA-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BS1_Supporting

The NM_000348.4(SRD5A2):c.*1152del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00644 in 191,082 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.021 (0 hom.)
• Consequence: SRD5A2 NM_000348.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.414

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0211 (1048/49730) while in subpopulation AFR AF= 0.0265 (58/2186). AF 95% confidence interval is 0.0211. There are 0 homozygotes in gnomad4_exome. There are 461 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRD5A2	NM_000348.4	c.*1152del		3_prime_UTR_variant	5/5	ENST00000622030.2
SRD5A2	XM_011533069.3	c.*1152del		3_prime_UTR_variant	5/5
SRD5A2	XM_011533072.3	c.*1152del		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRD5A2	ENST00000622030.2	c.*1152del		3_prime_UTR_variant	5/5	1	NM_000348.4	P1

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 180 AN: 141304 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00280

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000637

Gnomad ASJ AF: 0.00121

Gnomad EAS AF: 0.00101

Gnomad SAS AF: 0.000898

Gnomad FIN AF: 0.000818

Gnomad MID AF: 0.00336

Gnomad NFE AF: 0.000576

Gnomad OTH AF: 0.00263

GnomAD4 exome AF: 0.0211 AC: 1048 AN: 49730 Hom.: 0 Cov.: 0 AF XY: 0.0200 AC XY: 461 AN XY: 23060

Gnomad4 AFR exome AF: 0.0265

Gnomad4 AMR exome AF: 0.0246

Gnomad4 ASJ exome AF: 0.0211

Gnomad4 EAS exome AF: 0.0163

Gnomad4 SAS exome AF: 0.0220

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0222

Gnomad4 OTH exome AF: 0.0178

GnomAD4 genome AF: 0.00129 AC: 182 AN: 141352 Hom.: 0 Cov.: 32 AF XY: 0.00130 AC XY: 89 AN XY: 68518

Gnomad4 AFR AF: 0.00282

Gnomad4 AMR AF: 0.000636

Gnomad4 ASJ AF: 0.00121

Gnomad4 EAS AF: 0.00101

Gnomad4 SAS AF: 0.000901

Gnomad4 FIN AF: 0.000818

Gnomad4 NFE AF: 0.000576

Gnomad4 OTH AF: 0.00313

Alfa AF: 0.000110 Hom.: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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: rs74702388; hg19: chr2-31750113;