rs121908184

chr1-25800231-A-Gchr1-25800231-A-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 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:5
• Conservation: PhyloP100: -3.59

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]

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_020451.3 (SELENON) was described as [Pathogenic] in ClinVar as 1701096
• PM2: Very rare variant in population databases, with high coverage
• 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. Variant chr1-25800231-A-G is described in Lovd as [Pathogenic]. Variant chr1-25800231-A-G is described in Lovd as [Pathogenic]. Variant chr1-25800231-A-G is described in Lovd as [Benign]. Variant chr1-25800231-A-G is described in Lovd as [Likely_pathogenic]. Variant chr1-25800231-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SELENON	NM_020451.3	c.1A>G	p.Met1?	start_lost	1/13	ENST00000361547.7
SELENON	NM_206926.2	c.1A>G	p.Met1?	start_lost	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SELENON	ENST00000361547.7	c.1A>G	p.Met1?	start_lost	1/13	1	NM_020451.3
SELENON	ENST00000374315.1	c.1A>G	p.Met1?	start_lost	1/12	5		P1
SELENON	ENST00000354177.9	c.1A>G	p.Met1?	start_lost	1/12	5
SELENON	ENST00000494537.2	c.1A>G	p.Met1?	start_lost, NMD_transcript_variant	1/13	3

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000378

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000527

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000929

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000340

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Eichsfeld type congenital muscular dystrophy Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Feb 04, 2023	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

Pathogenic, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Nov 15, 2021

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2015

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 15, 2021

- -

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
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
MutationTaster	Benign	1.0	A;A;A
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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91

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

Other links and lift over

dbSNP: rs121908184; hg19: chr1-26126722;