4-55346253-G-C

Position:

• chr4-55346253-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_024592.5(SRD5A3):​c.-84G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 1,171,582 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (8 hom.)
• Consequence: SRD5A3 NM_024592.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.908

Genes affected

SRD5A3 (HGNC:25812): (steroid 5 alpha-reductase 3) The protein encoded by this gene belongs to the steroid 5-alpha reductase family, and polyprenol reductase subfamily. It is involved in the production of androgen 5-alpha-dihydrotestosterone (DHT) from testosterone, and maintenance of the androgen-androgen receptor activation pathway. This protein is also necessary for the conversion of polyprenol into dolichol, which is required for the synthesis of dolichol-linked monosaccharides and the oligosaccharide precursor used for N-linked glycosylation of proteins. Mutations in this gene are associated with congenital disorder of glycosylation type Iq. [provided by RefSeq, Mar 2011]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00217 (322/148614) while in subpopulation NFE AF= 0.00348 (229/65750). AF 95% confidence interval is 0.00311. There are 2 homozygotes in gnomad4. There are 134 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
SRD5A3	NM_024592.5	c.-84G>C		5_prime_UTR_variant	1/5	ENST00000264228.9
SRD5A3	NM_001410732.1	c.-84G>C		5_prime_UTR_variant	1/4
SRD5A3	XM_005265767.4	c.-84G>C		5_prime_UTR_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRD5A3	ENST00000264228.9	c.-84G>C		5_prime_UTR_variant	1/5	1	NM_024592.5	P1
SRD5A3	ENST00000679836.1	c.-84G>C		5_prime_UTR_variant	1/4

Frequencies

GnomAD3 genomes AF: 0.00217 AC: 322 AN: 148504 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00102

Gnomad AMI AF: 0.0124

Gnomad AMR AF: 0.00215

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.000293

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00348

Gnomad OTH AF: 0.00198

GnomAD4 exome AF: 0.00303 AC: 3102 AN: 1022968 Hom.: 8 Cov.: 16 AF XY: 0.00293 AC XY: 1466 AN XY: 500154

Gnomad4 AFR exome AF: 0.000666

Gnomad4 AMR exome AF: 0.00202

Gnomad4 ASJ exome AF: 0.000139

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000113

Gnomad4 FIN exome AF: 0.000766

Gnomad4 NFE exome AF: 0.00356

Gnomad4 OTH exome AF: 0.00176

GnomAD4 genome AF: 0.00217 AC: 322 AN: 148614 Hom.: 2 Cov.: 32 AF XY: 0.00184 AC XY: 134 AN XY: 72638

Gnomad4 AFR AF: 0.00102

Gnomad4 AMR AF: 0.00215

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.000293

Gnomad4 NFE AF: 0.00348

Gnomad4 OTH AF: 0.00196

Alfa AF: 0.0000531 Hom.: 0

Bravo AF: 0.00249

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

SRD5A3-congenital disorder of glycosylation Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.2
DANN	Benign	0.57

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: rs532409901; hg19: chr4-56212420;