4-55346393-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_024592.5(SRD5A3):c.57G>A(p.Trp19*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00006 in 1,584,474 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000061 ( 0 hom. )

Consequence

SRD5A3
NM_024592.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 2.80

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:

ENSG00000288695 (HGNC:):

ENSG00000288695 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-55346393-G-A is Pathogenic according to our data. Variant chr4-55346393-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 96125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-55346393-G-A is described in Lovd as [Pathogenic]. Variant chr4-55346393-G-A is described in Lovd as [Pathogenic]. Variant chr4-55346393-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRD5A3	NM_024592.5 link	c.57G>A	p.Trp19*	stop_gained	Exon 1 of 5	ENST00000264228.9	NP_078868.1	Q9H8P0
SRD5A3	NM_001410732.1 link	c.57G>A	p.Trp19*	stop_gained	Exon 1 of 4		NP_001397661.1
SRD5A3	XM_005265767.4 link	c.57G>A	p.Trp19*	stop_gained	Exon 1 of 3		XP_005265824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRD5A3	ENST00000264228.9 link	c.57G>A	p.Trp19*	stop_gained	Exon 1 of 5	1	NM_024592.5	ENSP00000264228.4		Q9H8P0
ENSG00000288695	ENST00000679707.1 link	c.57G>A	p.Trp19*	stop_gained	Exon 1 of 6			ENSP00000505713.1		A0A7P0T9P9

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000118

AC:

AN:

195484

Hom.:

AF XY:

0.000193

AC XY:

AN XY:

108846

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000793

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000237

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000607

AC:

AN:

1432222

Hom.:

Cov.:

AF XY:

0.0000886

AC XY:

AN XY:

711210

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000919

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000455

Gnomad4 OTH exome

AF:

0.000101

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.000118

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

SRD5A3-congenital disorder of glycosylation

Pathogenic:5

Nov 12, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Trp19*) in the SRD5A3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SRD5A3 are known to be pathogenic (PMID: 20637498, 20700148, 31638560). This variant is present in population databases (rs398124401, ExAC 0.1%). This variant has been observed in individual(s) with SRD5A3-congenital disorder of glycosylation (PMID: 24433453, 28940310, 20852264). ClinVar contains an entry for this variant (Variation ID: 96125). For these reasons, this variant has been classified as Pathogenic. -

Sep 01, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as disease-causing and was found once in our laboratory homozygous in a 5-year-old male with intellectual disability, hypotonia, ataxia, abnormal movements, dysmorphic features, microcephaly, failure to thrive, optic nerve atrophy, and a duplicated left kidney. Heterozygotes are expected to be asymptomatic carriers -

Jul 15, 2017

Centre for Arab Genomic Studies, Sheikh Hamdan Award for Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lifecell International Pvt. Ltd

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A Heterozygous Nonsense variant c.57G>A in Exon 1 of the SRD5A3 gene that results in the amino acid substitution p.Trp19* was identified. The observed variant has a minimum allele frequency of 0.00012/% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (variant ID 96125). This variant has been observed in many individuals affected with Congenital disorder of glycosylation reported by Bastaki F et al., 2018). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. -

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The stop gained p.W19* in SRD5A3 (NM_024592.4) has been reported in the homozygous state in affected patients(Morava et al., 2010;Gupta N et al,2018) . The variant has been classified as Pathogenic in the ClinVar database. It is observed in heterozygous state in 21/26490 (0.0793%) alleles from individuals of South Asian background in the gnomAD dataset.This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic. -

Kahrizi syndrome

Pathogenic:3

Genomics England Pilot Project, Genomics England

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 09, 2024

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous nonsense variant in exon 1 of the SRD5A3 gene that results in a stop codon and premature truncation of the protein at codon 19 (p.Trp19Ter) was detected. The observed variant has previously been reported in patients affected with cerebello-ocular syndrome with abnormal glycosylation [PMID: 20852264]. The p.Trp19Ter variant has a minor allele frequency of 0.03%, 0.005%, 0.01% and 0.002% in the 1000 genomes, gnomAD (v3.1), gnomdAD (v2.1) and topmed databases respectively. The in-silico prediction of the variant is damaging by MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. -

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PVS1,PM3 (very strong),PM2 -

not provided

Pathogenic:3

Jan 25, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 14, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29998879, 33879512, 34758253, 32581362, 24433453, 22304929, 20852264, 27480077, 28253385, 28940310, 28771251, 27457812, 25326635, 30315573, 30653986, 31980526, 31319225, 35725860) -

Jan 11, 2024

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SRD5A3-related disorder

Pathogenic:1

Jan 01, 2024

Daryl Scott Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2 -

Autism;C0557874:Global developmental delay;C0730290:Cone dystrophy

Pathogenic:1

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Congenital disorder of glycosylation

Pathogenic:1

Jul 08, 2016

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Abnormality of the nervous system

Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Benign

0.20

Vest4

0.077

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

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