rs779162837

Variant names:

• chr1-25813899-G-A
• rs779162837
• NM_020451.3:c.1406G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-25813899-G-A
• chr1-25813899-G-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM5 PP3_Moderate PP5_Very_Strong

The NM_020451.3(SELENON):​c.1406G>A​(p.Arg469Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,716 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R469W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: SELENON NM_020451.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.77
• Publications: 7 publications found

Genes affected

SELENON (HGNC:15999): (selenoprotein N) This gene encodes a glycoprotein that is localized in the endoplasmic reticulum. It plays an important role in cell protection against oxidative stress, and in the regulation of redox-related calcium homeostasis. Mutations in this gene are associated with early onset muscle disorders, referred to as SEPN1-related myopathy. SEPN1-related myopathy consists of 4 autosomal recessive disorders, originally thought to be separate entities: rigid spine muscular dystrophy (RSMD1), the classical form of multiminicore disease, desmin related myopathy with Mallory-body like inclusions, and congenital fiber-type disproportion (CFTD). This protein is a selenoprotein, containing the rare amino acid selenocysteine (Sec). Sec is encoded by the UGA codon, which normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, designated the Sec insertion sequence (SECIS) element, that is necessary for the recognition of UGA as a Sec codon, rather than as a stop signal. A second stop-codon redefinition element (SRE) adjacent to the UGA codon has been identified in this gene (PMID:15791204). SRE is a phylogenetically conserved stem-loop structure that stimulates readthrough at the UGA codon, and augments the Sec insertion efficiency by SECIS. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2016]

SELENON Gene-Disease associations (from GenCC):

• rigid spine muscular dystrophy 1

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics, G2P
• SELENON-related myopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• congenital myopathy 4A, autosomal dominant

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• congenital fiber-type disproportion myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• desmin-related myopathy with Mallory body-like inclusions

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• rigid spine syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000255054 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_020451.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-25813898-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 571063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.88
• PP5: Variant 1-25813899-G-A is Pathogenic according to our data. Variant chr1-25813899-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 461629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SELENON	NM_020451.3	c.1406G>A	p.Arg469Gln	missense_variant	Exon 11 of 13	ENST00000361547.7	NP_065184.2
SELENON	NM_206926.2	c.1304G>A	p.Arg435Gln	missense_variant	Exon 10 of 12		NP_996809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SELENON	ENST00000361547.7	c.1406G>A	p.Arg469Gln	missense_variant	Exon 11 of 13	1	NM_020451.3	ENSP00000355141.2
ENSG00000255054	ENST00000527604.1	n.-74G>A		upstream_gene_variant		5		ENSP00000457066.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 249326 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000223

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461716 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727154

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111904

Other (OTH) AF: 0.0000166 AC: 1 AN: 60390

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Eichsfeld type congenital muscular dystrophy Pathogenic:4

Mar 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 24, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.1406G>A (p.Arg469Gln) variant in SELENON gene has been reported previously with autosomal recessive inheritance in individuals affected with SELENON-related disorders (Maiti et al. 2009; Bachmann et al. 2019; Tsang et al. 2020). The p.Arg469Gln variant is reported with an allele frequency of 0.002% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. The amino acid change p.Arg469Gln in SELENON is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant has been reported to the ClinVar database as Pathogenic / Likely Pathogenic. The amino acid Arg at position 469 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. Missense change in this region is reported to affect the protein function (Maiti et al. 2009). Additional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic. -

Jan 24, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Arg469Gln variant in SELENON has been reported in 6 individuals with SELENON-RM (PMID: 32154989, 19067361, 34867752, 30932294, Concentino_2016) and has been identified in 0.02% (4/17976) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs779162837). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 461629) and has been interpreted as pathogenic by Invitae. Of the 6 affected individuals, 2 of those were homozygotes, and 1 was a compound heterozygote that carried a reported likely pathogenic variant with unknown phase, which increases the likelihood that the p.Arg469Gln variant is pathogenic (PMID: 32154989, 19067361). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg469Gln variant is uncertain. ACMG/AMP Criteria applied: PP3, PM3 (Richards 2015). -

Dec 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 469 of the SELENON protein (p.Arg469Gln). This variant is present in population databases (no rsID available, gnomAD 0.02%). This missense change has been observed in individual(s) with SELENON-related myopathy (PMID: 19067361, 30932294, 32154989; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg435Gln. ClinVar contains an entry for this variant (Variation ID: 461629). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SELENON protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.39	.;T;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	2.0	.;M;.
PhyloP100		7.8
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.7	D;N;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.95, 0.97	.;P;D
Vest4		0.99
MutPred		0.76		.;Loss of phosphorylation at T471 (P = 0.1135);.;
MVP		0.95
MPC		0.93
ClinPred		0.74	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.56
Mutation Taster		=8/92	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs779162837; hg19: chr1-26140390;