4-55346297-G-A

Variant summary

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

The NM_024592.5(SRD5A3):c.-40G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00259 in 1,368,586 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (45 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (36 hom.)
• Consequence: SRD5A3 NM_024592.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.143

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 4-55346297-G-A is Benign according to our data. Variant chr4-55346297-G-A is described in ClinVar as [Benign]. Clinvar id is 349004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.05 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRD5A3	NM_024592.5	c.-40G>A		5_prime_UTR_variant	1/5	ENST00000264228.9
SRD5A3	NM_001410732.1	c.-40G>A		5_prime_UTR_variant	1/4
SRD5A3	XM_005265767.4	c.-40G>A		5_prime_UTR_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRD5A3	ENST00000264228.9	c.-40G>A		5_prime_UTR_variant	1/5	1	NM_024592.5	P1
SRD5A3	ENST00000679836.1	c.-40G>A		5_prime_UTR_variant	1/4

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2060 AN: 152132 Hom.: 45 Cov.: 32

Gnomad AFR AF: 0.0475

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00272 AC: 30 AN: 11022 Hom.: 1 AF XY: 0.00142 AC XY: 9 AN XY: 6332

Gnomad AFR exome AF: 0.0779

Gnomad AMR exome AF: 0.00517

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00121 AC: 1473 AN: 1216346 Hom.: 36 Cov.: 28 AF XY: 0.00104 AC XY: 616 AN XY: 592004

Gnomad4 AFR exome AF: 0.0525

Gnomad4 AMR exome AF: 0.00387

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000579

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000221

Gnomad4 OTH exome AF: 0.00301

GnomAD4 genome AF: 0.0136 AC: 2067 AN: 152240 Hom.: 45 Cov.: 32 AF XY: 0.0134 AC XY: 1001 AN XY: 74436

Gnomad4 AFR AF: 0.0476

Gnomad4 AMR AF: 0.00458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.0103 Hom.: 6

Bravo AF: 0.0150

Asia WGS AF: 0.00232 AC: 9 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 28, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

SRD5A3-congenital disorder of glycosylation Benign:1

Benign, 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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	14
Dann	Benign	0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0

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: rs111568566; hg19: chr4-56212464;