1-25800231-A-G

Variant names:

• chr1-25800231-A-G
• rs121908184
• NM_020451.3:c.1A>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PS1_Moderate PP5_Very_Strong

The NM_020451.3(SELENON):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000484 in 764,690 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.000042 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: SELENON NM_020451.3 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: -3.59
• Publications: 9 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

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 27 pathogenic variants. Next in-frame start position is after 85 codons. Genomic position: 25801112. Lost 0.143 part of the original CDS.
• PS1: Another start lost variant in NM_020451.3 (SELENON) was described as [Likely_pathogenic] in ClinVar as 373075
• PP5: Variant 1-25800231-A-G is Pathogenic according to our data. Variant chr1-25800231-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4491.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.1A>G	p.Met1?	start_lost	Exon 1 of 13	ENST00000361547.7	NP_065184.2
SELENON	NM_206926.2	c.1A>G	p.Met1?	start_lost	Exon 1 of 12		NP_996809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SELENON	ENST00000361547.7	c.1A>G	p.Met1?	start_lost	Exon 1 of 13	1	NM_020451.3	ENSP00000355141.2
SELENON	ENST00000374315.1	c.1A>G	p.Met1?	start_lost	Exon 1 of 12	5		ENSP00000363434.1
SELENON	ENST00000354177.9	c.1A>G	p.Met1?	start_lost	Exon 1 of 12	5		ENSP00000346109.5
SELENON	ENST00000494537.2	n.1A>G		non_coding_transcript_exon_variant	Exon 1 of 13	3		ENSP00000508308.1

Frequencies

GnomAD3 genomes AF: 0.0000422 AC: 6 AN: 142032 Hom.: 0 Cov.: 30

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000929

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000498 AC: 31 AN: 622658 Hom.: 0 Cov.: 8 AF XY: 0.0000483 AC XY: 14 AN XY: 289794

African (AFR) AF: 0.00 AC: 0 AN: 11754

American (AMR) AF: 0.00 AC: 0 AN: 730

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3846

East Asian (EAS) AF: 0.000378 AC: 1 AN: 2644

South Asian (SAS) AF: 0.00 AC: 0 AN: 13012

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1234

European-Non Finnish (NFE) AF: 0.0000527 AC: 30 AN: 568852

Other (OTH) AF: 0.00 AC: 0 AN: 20376

GnomAD4 genome AF: 0.0000422 AC: 6 AN: 142032 Hom.: 0 Cov.: 30 AF XY: 0.0000580 AC XY: 4 AN XY: 68938

African (AFR) AF: 0.00 AC: 0 AN: 39652

American (AMR) AF: 0.00 AC: 0 AN: 14384

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3352

East Asian (EAS) AF: 0.00 AC: 0 AN: 4762

South Asian (SAS) AF: 0.00 AC: 0 AN: 4422

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7736

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.0000929 AC: 6 AN: 64572

Other (OTH) AF: 0.00 AC: 0 AN: 1956

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Eichsfeld type congenital muscular dystrophy Pathogenic:3

Apr 29, 2025

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The heterozygous p.Met1Val variant in SELENON has been reported in at least 7 individuals with rigid spine muscular dystrophy 1 (PMID: 12192640, 16365872, 23394784, 28558865), and has been identified in 0.013% (17406) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121908184). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has been reported in ClinVar (VCV000004491.15) and has been interpreted as pathogenic/likely pathogenic by multiple submitters. Of the 7 affected individuals, 2 were compound heterozygotes that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Met1Val variant is pathogenic (VCV000373075.21; PMID: 16365872, 28558865). This variant is located in the first amino acid and abolishes the methionine initiation codon. The next in-frame methionine is at amino acid residue 85 and there are multiple reported pathogenic/likely pathogenic variants in ClinVar upstream of this downstream methionine. Loss of function of the SELENON gene is an established disease mechanism in autosomal recessive rigid spine muscular dystrophy 1. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive rigid spine muscular dystrophy 1. ACMG/AMP Criteria PM3_strong, PVS1_moderate, PM2_supporting (Richards 2015). -

Mar 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the SELENON mRNA. The next in-frame methionine is located at codon 85. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of the initiator codon has been observed in individuals with SELENON-related conditions (PMID: 12192640, 23394784, 28558865). ClinVar contains an entry for this variant (Variation ID: 4491). For these reasons, this variant has been classified as Pathogenic. -

Congenital myopathy with fiber type disproportion Pathogenic:1

Nov 15, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jun 26, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1 A>G variant in the SEPN1 gene has been identified previously, both in the compound heterozygousand homozygous state, in patients with SEPN1-related disorders. Patient's presented with multiple featuresincluding rigid spine, nasal speech and various histological findings including minicores (Ferreiro et al., 2002;Maggi et al., 2013). The variant alters the initiator Methionine codon, and the resultant protein would bedescribed as p.Met1?" to signify that it is not known if the loss of Met1 means that all protein translation iscompletely prevented or if an abnormal protein is produced using an alternate Methionine initiator codon.Therefore, c.1 A>G is considered a pathogenic variant." -

Eichsfeld type congenital muscular dystrophy;C0546264:Congenital myopathy with fiber type disproportion Pathogenic:1

Nov 15, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely 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	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	8.1
DANN	Benign	0.97
DEOGEN2	Benign	0.045	.;T;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.027	N
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	-0.12	T
PhyloP100		-3.6
PROVEAN	Benign	-0.14	N;N;N
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.14, 0.22	.;B;B
Vest4		0.69
MutPred		1.0		Gain of MoRF binding (P = 0.1776);Gain of MoRF binding (P = 0.1776);Gain of MoRF binding (P = 0.1776);
MVP		0.88
ClinPred		0.95	D
GERP RS		2.0
PromoterAI		-0.36	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
Mutation Taster		=7/193	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: rs121908184; hg19: chr1-26126722;