1-25800231-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PS1_ModeratePP5_Very_Strong

The ENST00000361547.7(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
ENST00000361547.7 start_lost

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: -3.59

Publications

9 publications found

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 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

SELENON links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 ENST00000361547.7 (SELENON) was described as [Likely_pathogenic] in ClinVar

PP5

Variant 1-25800231-A-G is Pathogenic according to our data. Variant chr1-25800231-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4491.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361547.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SELENON	NM_020451.3	MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 13	NP_065184.2
	SELENON	NM_206926.2		c.1A>G	p.Met1?	start_lost	Exon 1 of 12	NP_996809.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SELENON	ENST00000361547.7	TSL:1 MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 13	ENSP00000355141.2
SELENON	ENST00000374315.1	TSL:5	c.1A>G	p.Met1?	start_lost	Exon 1 of 12	ENSP00000363434.1
SELENON	ENST00000354177.9	TSL:5	c.1A>G	p.Met1?	start_lost	Exon 1 of 12	ENSP00000346109.5

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

African (AFR)

AF:

0.00

AC:

AN:

11754

American (AMR)

AF:

0.00

AC:

AN:

730

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3846

East Asian (EAS)

AF:

0.000378

AC:

AN:

2644

South Asian (SAS)

AF:

0.00

AC:

AN:

13012

European-Finnish (FIN)

AF:

0.00

AC:

AN:

210

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1234

European-Non Finnish (NFE)

AF:

0.0000527

AC:

AN:

568852

Other (OTH)

AF:

0.00

AC:

AN:

20376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000422

AC:

AN:

142032

Hom.:

Cov.:

AF XY:

0.0000580

AC XY:

AN XY:

68938

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

39652

American (AMR)

AF:

0.00

AC:

AN:

14384

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3352

East Asian (EAS)

AF:

0.00

AC:

AN:

4762

South Asian (SAS)

AF:

0.00

AC:

AN:

4422

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7736

Middle Eastern (MID)

AF:

0.00

AC:

AN:

304

European-Non Finnish (NFE)

AF:

0.0000929

AC:

AN:

64572

Other (OTH)

AF:

0.00

AC:

AN:

1956

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000340

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Eichsfeld type congenital muscular dystrophy (5)

Congenital myopathy with fiber type disproportion (1)

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

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Benign

8.1

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.045

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.027

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

-0.12

PhyloP100

-3.6

PROVEAN

Benign

-0.14

REVEL

Uncertain

0.51

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.14

Vest4

0.69

MutPred

1.0

Gain of MoRF binding (P = 0.1776)

MVP

0.88

ClinPred

0.95

GERP RS

2.0

PromoterAI

-0.36

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

Mutation Taster

=7/193

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over