rs115852080

Positions:

chr1-25808625-G-A

Variant summary

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

The NM_020451.3(SELENON):c.583G>A(p.Ala195Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,613,668 control chromosomes in the GnomAD database, including 194 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 28 hom., cov: 33)

Exomes 𝑓: 0.013 ( 166 hom. )

Consequence

SELENON
NM_020451.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 3.25

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=0.004422933).

BP6

Variant 1-25808625-G-A is Benign according to our data. Variant chr1-25808625-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-25808625-G-A is described in Lovd as [Benign]. Variant chr1-25808625-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-25808625-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0106 (1611/152086) while in subpopulation NFE AF= 0.015 (1017/67920). AF 95% confidence interval is 0.0142. There are 28 homozygotes in gnomad4. There are 711 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SELENON	NM_020451.3 linkuse as main transcript	c.583G>A	p.Ala195Thr	missense_variant	5/13	ENST00000361547.7	NP_065184.2	Q9NZV5-1
SELENON	NM_206926.2 linkuse as main transcript	c.481G>A	p.Ala161Thr	missense_variant	4/12		NP_996809.1	Q9NZV5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SELENON	ENST00000361547.7 linkuse as main transcript	c.583G>A	p.Ala195Thr	missense_variant	5/13	1	NM_020451.3	ENSP00000355141.2	Q9NZV5-1
SELENON	ENST00000374315.1 linkuse as main transcript	c.481G>A	p.Ala161Thr	missense_variant	4/12	5		ENSP00000363434.1	Q9NZV5-2
SELENON	ENST00000354177.9 linkuse as main transcript	c.481G>A	p.Ala161Thr	missense_variant	4/12	5		ENSP00000346109.5	H9KV50
SELENON	ENST00000494537.2 linkuse as main transcript	n.481G>A		non_coding_transcript_exon_variant	4/13	3		ENSP00000508308.1	A0A804HLD6

Frequencies

GnomAD3 genomes

AF:

0.0106

AC:

1610

AN:

151968

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00464

Gnomad AMI

AF:

0.142

Gnomad AMR

AF:

0.00884

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00849

Gnomad FIN

AF:

0.00170

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0150

Gnomad OTH

AF:

0.0134

GnomAD3 exomes

AF:

0.0101

AC:

2498

AN:

248090

Hom.:

AF XY:

0.0106

AC XY:

1434

AN XY:

134786

show subpopulations

Gnomad AFR exome

AF:

0.00498

Gnomad AMR exome

AF:

0.00742

Gnomad ASJ exome

AF:

0.0110

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.00925

Gnomad FIN exome

AF:

0.00266

Gnomad NFE exome

AF:

0.0145

Gnomad OTH exome

AF:

0.0141

GnomAD4 exome

AF:

0.0133

AC:

19496

AN:

1461582

Hom.:

166

Cov.:

AF XY:

0.0134

AC XY:

9765

AN XY:

727110

show subpopulations

Gnomad4 AFR exome

AF:

0.00523

Gnomad4 AMR exome

AF:

0.00787

Gnomad4 ASJ exome

AF:

0.0108

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00920

Gnomad4 FIN exome

AF:

0.00250

Gnomad4 NFE exome

AF:

0.0152

Gnomad4 OTH exome

AF:

0.0131

GnomAD4 genome

AF:

0.0106

AC:

1611

AN:

152086

Hom.:

Cov.:

AF XY:

0.00956

AC XY:

711

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00465

Gnomad4 AMR

AF:

0.00883

Gnomad4 ASJ

AF:

0.0118

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00850

Gnomad4 FIN

AF:

0.00170

Gnomad4 NFE

AF:

0.0150

Gnomad4 OTH

AF:

0.0132

Alfa

AF:

0.0137

Hom.:

Bravo

AF:

0.0114

TwinsUK

AF:

0.00971

AC:

ALSPAC

AF:

0.0145

AC:

ESP6500AA

AF:

0.00510

AC:

ESP6500EA

AF:

0.0155

AC:

130

ExAC

AF:

0.00999

AC:

1208

Asia WGS

AF:

0.00779

AC:

AN:

3478

EpiCase

AF:

0.0176

EpiControl

AF:

0.0165

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 02, 2020	p.Ala195Thr in exon 5 of SEPN1: This variant is not expected to have clinical significance because it has been identified in 1.4% (907/66106) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs115852080). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 13, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 07, 2012	- -
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. -

not provided

Benign:5

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	SELENON: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 10, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

SEPN1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

-0.27

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

.;T;.

Eigen

Benign

-0.048

Eigen_PC

Benign

-0.044

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.82

T;T;T

MetaRNN

Benign

0.0044

T;T;T

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

1.1

.;L;.

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.3

N;N;N

REVEL

Uncertain

0.40

Sift

Benign

0.059

T;T;T

Sift4G

Benign

0.44

T;T;T

Polyphen

0.95, 0.97

.;P;D

Vest4

0.34

MVP

0.92

MPC

0.28

ClinPred

0.015

GERP RS

4.0

Varity_R

0.056

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