rs115852080

chr1-25808625-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 3.25

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 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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SELENON	NM_020451.3	c.583G>A	p.Ala195Thr	missense_variant	5/13	ENST00000361547.7
SELENON	NM_206926.2	c.481G>A	p.Ala161Thr	missense_variant	4/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SELENON	ENST00000361547.7	c.583G>A	p.Ala195Thr	missense_variant	5/13	1	NM_020451.3
SELENON	ENST00000374315.1	c.481G>A	p.Ala161Thr	missense_variant	4/12	5		P1
SELENON	ENST00000354177.9	c.481G>A	p.Ala161Thr	missense_variant	4/12	5
SELENON	ENST00000494537.2	c.481G>A	p.Ala161Thr	missense_variant, NMD_transcript_variant	4/13	3

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1610 AN: 151968 Hom.: 28 Cov.: 33

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.: 28 AF XY: 0.0106 AC XY: 1434 AN XY: 134786

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.: 32 AF XY: 0.0134 AC XY: 9765 AN XY: 727110

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.: 28 Cov.: 33 AF XY: 0.00956 AC XY: 711 AN XY: 74348

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.: 11

Bravo AF: 0.0114

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.0145 AC: 56

ESP6500AA AF: 0.00510 AC: 21

ESP6500EA AF: 0.0155 AC: 130

ExAC AF: 0.00999 AC: 1208

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.0176

EpiControl AF: 0.0165

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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). -
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	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	Eurofins Ntd Llc (ga)	Sep 07, 2012	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SELENON: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 10, 2017	- -
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

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	20
Dann	Uncertain	0.99
Eigen	Benign	-0.048
Eigen_PC	Benign	-0.044
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T;T;T
MetaRNN	Benign	0.0044	T;T;T
MetaSVM	Uncertain	-0.18	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.43	T
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	T
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

Other links and lift over

dbSNP: rs115852080; hg19: chr1-26135116; COSMIC: COSV99052738; COSMIC: COSV99052738;