rs61733673

Positions:

chr4-55370059-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024592.5(SRD5A3):c.925C>G(p.His309Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00254 in 1,614,010 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 45 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 52 hom. )

Consequence

SRD5A3
NM_024592.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.20

Variant links:

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 links:

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

SRD5A3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014054894).

BP6

Variant 4-55370059-C-G is Benign according to our data. Variant chr4-55370059-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 349008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0137 (2079/152270) while in subpopulation AFR AF= 0.0479 (1990/41540). AF 95% confidence interval is 0.0462. There are 45 homozygotes in gnomad4. There are 1012 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 45 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SRD5A3	NM_024592.5 linkuse as main transcript	c.925C>G	p.His309Asp	missense_variant	5/5	ENST00000264228.9	NP_078868.1
SRD5A3-AS1	NR_037969.1 linkuse as main transcript	n.364-2896G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SRD5A3	ENST00000264228.9 linkuse as main transcript	c.925C>G	p.His309Asp	missense_variant	5/5	1	NM_024592.5	ENSP00000264228	P1

Frequencies

GnomAD3 genomes

AF:

0.0136

AC:

2072

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0479

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00445

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00343

AC:

861

AN:

251164

Hom.:

AF XY:

0.00251

AC XY:

341

AN XY:

135718

show subpopulations

Gnomad AFR exome

AF:

0.0479

Gnomad AMR exome

AF:

0.00214

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.00138

AC:

2015

AN:

1461740

Hom.:

Cov.:

AF XY:

0.00115

AC XY:

838

AN XY:

727178

show subpopulations

Gnomad4 AFR exome

AF:

0.0512

Gnomad4 AMR exome

AF:

0.00233

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.00272

GnomAD4 genome

AF:

0.0137

AC:

2079

AN:

152270

Hom.:

Cov.:

AF XY:

0.0136

AC XY:

1012

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.0479

Gnomad4 AMR

AF:

0.00444

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00387

Hom.:

Bravo

AF:

0.0153

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0461

AC:

203

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00421

AC:

511

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

SRD5A3-congenital disorder of glycosylation

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	- -
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. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 22, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 30, 2016

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.68

D;D

Eigen

Benign

0.077

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.77

T;T

MetaRNN

Benign

0.014

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.1

D;D

REVEL

Benign

0.084

Sift

Benign

0.043

D;T

Sift4G

Uncertain

0.030

D;D

Polyphen

0.85

P;.

Vest4

0.46

MVP

0.52

MPC

0.47

ClinPred

0.039

GERP RS

4.8

Varity_R

0.24

gMVP

0.71

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over