chr2-31525043-T-TAA

Position:

• chr2-31525043-T-TAA

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_000348.4(SRD5A2):​c.*1152_*1153insTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00478 in 190,274 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (2 hom., cov: 32)
  • Exomes 𝑓: 0.014 (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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0016 (226/141308) while in subpopulation SAS AF= 0.0435 (193/4438). AF 95% confidence interval is 0.0385. There are 2 homozygotes in gnomad4. There are 163 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRD5A2	NM_000348.4	c.*1152_*1153insTT		3_prime_UTR_variant	5/5	ENST00000622030.2
SRD5A2	XM_011533069.3	c.*1152_*1153insTT		3_prime_UTR_variant	5/5
SRD5A2	XM_011533072.3	c.*1152_*1153insTT		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRD5A2	ENST00000622030.2	c.*1152_*1153insTT		3_prime_UTR_variant	5/5	1	NM_000348.4	P1

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 229 AN: 141262 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000467

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000142

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000606

Gnomad SAS AF: 0.0440

Gnomad FIN AF: 0.000234

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000934

Gnomad OTH AF: 0.00105

GnomAD4 exome AF: 0.0140 AC: 684 AN: 48966 Hom.: 0 Cov.: 0 AF XY: 0.0132 AC XY: 299 AN XY: 22714

Gnomad4 AFR exome AF: 0.0157

Gnomad4 AMR exome AF: 0.0213

Gnomad4 ASJ exome AF: 0.0115

Gnomad4 EAS exome AF: 0.0111

Gnomad4 SAS exome AF: 0.0470

Gnomad4 FIN exome AF: 0.0250

Gnomad4 NFE exome AF: 0.0138

Gnomad4 OTH exome AF: 0.0158

GnomAD4 genome AF: 0.00160 AC: 226 AN: 141308 Hom.: 2 Cov.: 32 AF XY: 0.00238 AC XY: 163 AN XY: 68484

Gnomad4 AFR AF: 0.000466

Gnomad4 AMR AF: 0.000142

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000608

Gnomad4 SAS AF: 0.0435

Gnomad4 FIN AF: 0.000234

Gnomad4 NFE AF: 0.0000934

Gnomad4 OTH AF: 0.00104

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

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;