rs35019869

Positions:

chr1-25805147-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020451.3(SELENON):c.409A>G(p.Thr137Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 1,613,160 control chromosomes in the GnomAD database, including 198 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T137I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.012 ( 17 hom., cov: 32)

Exomes 𝑓: 0.015 ( 181 hom. )

Consequence

SELENON
NM_020451.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.958

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002190411).

BP6

Variant 1-25805147-A-G is Benign according to our data. Variant chr1-25805147-A-G is described in ClinVar as [Benign]. Clinvar id is 130284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-25805147-A-G is described in Lovd as [Likely_benign]. Variant chr1-25805147-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0121 (1842/151954) while in subpopulation NFE AF= 0.0179 (1214/67972). AF 95% confidence interval is 0.017. There are 17 homozygotes in gnomad4. There are 896 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SELENON	NM_020451.3 linkuse as main transcript	c.409A>G	p.Thr137Ala	missense_variant	4/13	ENST00000361547.7
SELENON	NM_206926.2 linkuse as main transcript	c.307A>G	p.Thr103Ala	missense_variant	3/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SELENON	ENST00000361547.7 linkuse as main transcript	c.409A>G	p.Thr137Ala	missense_variant	4/13	1	NM_020451.3		Q9NZV5-1
SELENON	ENST00000374315.1 linkuse as main transcript	c.307A>G	p.Thr103Ala	missense_variant	3/12	5		P1	Q9NZV5-2
SELENON	ENST00000354177.9 linkuse as main transcript	c.307A>G	p.Thr103Ala	missense_variant	3/12	5
SELENON	ENST00000494537.2 linkuse as main transcript	c.307A>G	p.Thr103Ala	missense_variant, NMD_transcript_variant	3/13	3

Frequencies

GnomAD3 genomes

AF:

0.0121

AC:

1842

AN:

151836

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00305

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0146

Gnomad ASJ

AF:

0.0308

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00687

Gnomad FIN

AF:

0.0102

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0179

Gnomad OTH

AF:

0.0125

GnomAD3 exomes

AF:

0.0129

AC:

3224

AN:

249060

Hom.:

AF XY:

0.0134

AC XY:

1809

AN XY:

135134

show subpopulations

Gnomad AFR exome

AF:

0.00265

Gnomad AMR exome

AF:

0.00846

Gnomad ASJ exome

AF:

0.0355

Gnomad EAS exome

AF:

0.000167

Gnomad SAS exome

AF:

0.00683

Gnomad FIN exome

AF:

0.0121

Gnomad NFE exome

AF:

0.0175

Gnomad OTH exome

AF:

0.0149

GnomAD4 exome

AF:

0.0153

AC:

22313

AN:

1461206

Hom.:

181

Cov.:

AF XY:

0.0151

AC XY:

11010

AN XY:

726870

show subpopulations

Gnomad4 AFR exome

AF:

0.00236

Gnomad4 AMR exome

AF:

0.00899

Gnomad4 ASJ exome

AF:

0.0341

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00725

Gnomad4 FIN exome

AF:

0.0120

Gnomad4 NFE exome

AF:

0.0168

Gnomad4 OTH exome

AF:

0.0149

GnomAD4 genome

AF:

0.0121

AC:

1842

AN:

151954

Hom.:

Cov.:

AF XY:

0.0121

AC XY:

896

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.00304

Gnomad4 AMR

AF:

0.0146

Gnomad4 ASJ

AF:

0.0308

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00687

Gnomad4 FIN

AF:

0.0102

Gnomad4 NFE

AF:

0.0179

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.0161

Hom.:

Bravo

AF:

0.0123

TwinsUK

AF:

0.0154

AC:

ALSPAC

AF:

0.0187

AC:

ESP6500AA

AF:

0.00225

AC:

ESP6500EA

AF:

0.0170

AC:

142

ExAC

AF:

0.0129

AC:

1553

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0183

EpiControl

AF:

0.0202

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 05, 2017	p.Thr137Ala in exon 4 of SEPN1: This variant is not expected to have clinical si gnificance because it has been identified in 1.9% (1268/67520) of European chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs35019869). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

SEPN1-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Eichsfeld type congenital muscular dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.080

.;T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.41

T;T;T

MetaRNN

Benign

0.0022

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

.;N;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.51

N;N;N

REVEL

Benign

0.040

Sift

Benign

0.52

T;T;T

Sift4G

Benign

0.77

T;T;T

Polyphen

0.0

.;B;B

Vest4

0.033

MPC

0.24

ClinPred

0.00059

GERP RS

0.60

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.041

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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