chr1-25800217-C-A

Variant names:

• chr1-25800217-C-A
• rs867555591
• NM_020451.3:c.-14C>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_020451.3(SELENON):​c.-14C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 672,744 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (10 hom., cov: 30)
  • Exomes 𝑓: 0.00039 (2 hom.)
• Consequence: SELENON NM_020451.3 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 B:1
• Conservation: PhyloP100: -0.615
• Publications: 0 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00585 (855/146052) while in subpopulation AFR AF = 0.0195 (797/40846). AF 95% confidence interval is 0.0184. There are 10 homozygotes in GnomAd4. There are 427 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 10 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SELENON	NM_020451.3	c.-14C>A		5_prime_UTR_variant	Exon 1 of 13	ENST00000361547.7	NP_065184.2
SELENON	NM_206926.2	c.-14C>A		5_prime_UTR_variant	Exon 1 of 12		NP_996809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SELENON	ENST00000361547.7	c.-14C>A		5_prime_UTR_variant	Exon 1 of 13	1	NM_020451.3	ENSP00000355141.2
SELENON	ENST00000374315.1	c.-14C>A		5_prime_UTR_variant	Exon 1 of 12	5		ENSP00000363434.1
SELENON	ENST00000354177.9	c.-14C>A		upstream_gene_variant		5		ENSP00000346109.5
SELENON	ENST00000494537.2	n.-14C>A		upstream_gene_variant		3		ENSP00000508308.1

Frequencies

GnomAD3 genomes AF: 0.00578 AC: 844 AN: 145980 Hom.: 10 Cov.: 30

Gnomad AFR AF: 0.0193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00265

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: 0.000107

Gnomad OTH AF: 0.00595

GnomAD4 exome AF: 0.000385 AC: 203 AN: 526692 Hom.: 2 Cov.: 6 AF XY: 0.000370 AC XY: 91 AN XY: 246118

African (AFR) AF: 0.0175 AC: 172 AN: 9816

American (AMR) AF: 0.00 AC: 0 AN: 620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3284

East Asian (EAS) AF: 0.00 AC: 0 AN: 2262

South Asian (SAS) AF: 0.00 AC: 0 AN: 10954

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 178

Middle Eastern (MID) AF: 0.000969 AC: 1 AN: 1032

European-Non Finnish (NFE) AF: 0.0000104 AC: 5 AN: 481358

Other (OTH) AF: 0.00145 AC: 25 AN: 17188

GnomAD4 genome AF: 0.00585 AC: 855 AN: 146052 Hom.: 10 Cov.: 30 AF XY: 0.00601 AC XY: 427 AN XY: 71056

African (AFR) AF: 0.0195 AC: 797 AN: 40846

American (AMR) AF: 0.00265 AC: 39 AN: 14718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3388

East Asian (EAS) AF: 0.00 AC: 0 AN: 5074

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.000107 AC: 7 AN: 65714

Other (OTH) AF: 0.00589 AC: 12 AN: 2038

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

SEPN1-related disorder Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Uncertain:1

Dec 20, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SELENON-related disorder Benign:1

Nov 11, 2021

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	9.8
DANN	Benign	0.88
PhyloP100		-0.61
PromoterAI		0.040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Mutation Taster		=295/5	polymorphism

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: rs867555591; hg19: chr1-26126708;