rs35496669

chr4-55367591-A-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_024592.5(SRD5A3):c.566A>C(p.Tyr189Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000184 in 1,614,084 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00096 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: SRD5A3 NM_024592.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 2.26

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]

SRD5A3-AS1 (HGNC:44138): (SRD5A3 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006423861).
• BP6: Variant 4-55367591-A-C is Benign according to our data. Variant chr4-55367591-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212303.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000958 (146/152356) while in subpopulation AFR AF= 0.00303 (126/41588). AF 95% confidence interval is 0.0026. There are 2 homozygotes in gnomad4. There are 68 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRD5A3	NM_024592.5	c.566A>C	p.Tyr189Ser	missense_variant	4/5	ENST00000264228.9
SRD5A3-AS1	NR_037969.1	n.364-428T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRD5A3	ENST00000264228.9	c.566A>C	p.Tyr189Ser	missense_variant	4/5	1	NM_024592.5	P1

Frequencies

GnomAD3 genomes AF: 0.000952 AC: 145 AN: 152238 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00301

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000315 AC: 79 AN: 251126 Hom.: 1 AF XY: 0.000199 AC XY: 27 AN XY: 135730

Gnomad AFR exome AF: 0.00369

Gnomad AMR exome AF: 0.000463

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: 0.00000881

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000103 AC: 151 AN: 1461728 Hom.: 1 Cov.: 32 AF XY: 0.000100 AC XY: 73 AN XY: 727154

Gnomad4 AFR exome AF: 0.00308

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000958 AC: 146 AN: 152356 Hom.: 2 Cov.: 32 AF XY: 0.000913 AC XY: 68 AN XY: 74510

Gnomad4 AFR AF: 0.00303

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000199 Hom.: 1

Bravo AF: 0.00125

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000371 AC: 45

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

SRD5A3-congenital disorder of glycosylation Uncertain:1 Benign: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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 27, 2023	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	SRD5A3: BP4, BS2 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 10, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	7.2
Dann	Benign	0.72
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.21
Sift	Benign	0.38	T
Sift4G	Benign	0.38	T
Polyphen		0.016	B
Vest4		0.48
MVP		0.42
MPC		0.35
ClinPred		0.022	T
GERP RS		5.5
Varity_R		0.089
gMVP		0.35

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: rs35496669; hg19: chr4-56233758;