chr1-25800231-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: -3.59

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 20 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 22 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 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 rank	MANE	Protein	UniProt
SELENON	NM_020451.3 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 13	ENST00000361547.7	NP_065184.2	Q9NZV5-1
SELENON	NM_206926.2 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 12		NP_996809.1	Q9NZV5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SELENON	ENST00000361547.7 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 13	1	NM_020451.3	ENSP00000355141.2	Q9NZV5-1
SELENON	ENST00000374315.1 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 12	5		ENSP00000363434.1	Q9NZV5-2
SELENON	ENST00000354177.9 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 12	5		ENSP00000346109.5	H9KV50
SELENON	ENST00000494537.2 link	n.1A>G		non_coding_transcript_exon_variant	Exon 1 of 13	3		ENSP00000508308.1	A0A804HLD6

Frequencies

GnomAD3 genomes

AF:

0.0000422

AC:

AN:

142032

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:

0.00

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:

AN:

622658

Hom.:

Cov.:

AF XY:

0.0000483

AC XY:

AN XY:

289794

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000378

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:

AN:

142032

Hom.:

Cov.:

AF XY:

0.0000580

AC XY:

AN XY:

68938

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:

0.00

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

LINK: link

Submissions by phenotype

Eichsfeld type congenital muscular dystrophy

Pathogenic:2

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

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

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Uncertain

-0.12

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

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

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