NM_000348.4:c.*1056G>C

Variant names:

• chr2-31525140-C-G
• rs28383085
• NM_000348.4:c.*1056G>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000348.4(SRD5A2):​c.*1056G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0431 in 220,364 control chromosomes in the GnomAD database, including 354 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (264 hom., cov: 32)
  • Exomes 𝑓: 0.042 (90 hom.)
• Consequence: SRD5A2 NM_000348.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.59

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-31525140-C-G is Benign according to our data. Variant chr2-31525140-C-G is described in ClinVar as [Benign]. Clinvar id is 335807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRD5A2	NM_000348.4	c.*1056G>C		3_prime_UTR_variant	Exon 5 of 5	ENST00000622030.2	NP_000339.2
SRD5A2	XM_011533069.3	c.*1056G>C		3_prime_UTR_variant	Exon 5 of 5		XP_011531371.1
SRD5A2	XM_011533072.3	c.*1056G>C		3_prime_UTR_variant	Exon 7 of 7		XP_011531374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRD5A2	ENST00000622030	c.*1056G>C		3_prime_UTR_variant	Exon 5 of 5	1	NM_000348.4	ENSP00000477587.1

Frequencies

GnomAD3 genomes AF: 0.0438 AC: 6652 AN: 152042 Hom.: 260 Cov.: 32

Gnomad AFR AF: 0.0115

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.0369

Gnomad FIN AF: 0.0181

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0533

Gnomad OTH AF: 0.0426

GnomAD4 exome AF: 0.0416 AC: 2840 AN: 68210 Hom.: 90 Cov.: 0 AF XY: 0.0409 AC XY: 1289 AN XY: 31550

Gnomad4 AFR exome AF: 0.00884

Gnomad4 AMR exome AF: 0.125

Gnomad4 ASJ exome AF: 0.0241

Gnomad4 EAS exome AF: 0.000297

Gnomad4 SAS exome AF: 0.0554

Gnomad4 FIN exome AF: 0.0556

Gnomad4 NFE exome AF: 0.0510

Gnomad4 OTH exome AF: 0.0479

GnomAD4 genome AF: 0.0438 AC: 6665 AN: 152154 Hom.: 264 Cov.: 32 AF XY: 0.0434 AC XY: 3230 AN XY: 74384

Gnomad4 AFR AF: 0.0114

Gnomad4 AMR AF: 0.125

Gnomad4 ASJ AF: 0.0216

Gnomad4 EAS AF: 0.00289

Gnomad4 SAS AF: 0.0376

Gnomad4 FIN AF: 0.0181

Gnomad4 NFE AF: 0.0533

Gnomad4 OTH AF: 0.0436

Alfa AF: 0.0470 Hom.: 112

Bravo AF: 0.0494

Asia WGS AF: 0.0340 AC: 120 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.23
DANN	Benign	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: rs28383085; hg19: chr2-31750210;