4-55346393-G-A

Position:

chr4-55346393-G-A

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.Trp19Ter) 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:13

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:

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/exons	MANE	Protein
SRD5A3	NM_024592.5 linkuse as main transcript	c.57G>A	p.Trp19Ter	stop_gained	1/5	ENST00000264228.9	NP_078868.1
SRD5A3	NM_001410732.1 linkuse as main transcript	c.57G>A	p.Trp19Ter	stop_gained	1/4		NP_001397661.1
SRD5A3	XM_005265767.4 linkuse as main transcript	c.57G>A	p.Trp19Ter	stop_gained	1/3		XP_005265824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
SRD5A3	ENST00000264228.9 linkuse as main transcript	c.57G>A	p.Trp19Ter	stop_gained	1/5	1	NM_024592.5	ENSP00000264228	P1
SRD5A3	ENST00000679836.1 linkuse as main transcript	c.57G>A	p.Trp19Ter	stop_gained	1/4			ENSP00000506601
SRD5A3	ENST00000505210.1 linkuse as main transcript			upstream_gene_variant		3		ENSP00000424714

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:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

SRD5A3-congenital disorder of glycosylation

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Arab Genomic Studies, Sheikh Hamdan Award for Medical Sciences	Jul 15, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	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 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 12, 2020	For these reasons, this variant has been classified as Pathogenic. 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). This variant is present in population databases (rs398124401, ExAC 0.1%). 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	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. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 11, 2024	- -

Kahrizi syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Feb 09, 2024	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. -

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

Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

- -

Congenital disorder of glycosylation

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

Jul 08, 2016

- -

Abnormality of the nervous system

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

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

MutationTaster

Benign

1.0

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