rs35019869

chr1-25805147-A-G

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.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. 12/17 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.958

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=0.002190411).
• 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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 AR gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0121 AC: 1842 AN: 151836 Hom.: 17 Cov.: 32

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.: 35 AF XY: 0.0134 AC XY: 1809 AN XY: 135134

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.: 31 AF XY: 0.0151 AC XY: 11010 AN XY: 726870

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.: 17 Cov.: 32 AF XY: 0.0121 AC XY: 896 AN XY: 74274

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.: 34

Bravo AF: 0.0123

TwinsUK AF: 0.0154 AC: 57

ALSPAC AF: 0.0187 AC: 72

ESP6500AA AF: 0.00225 AC: 9

ESP6500EA AF: 0.0170 AC: 142

ExAC AF: 0.0129 AC: 1553

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0183

EpiControl AF: 0.0202

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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	-	- -

SEPN1-Related Disorders 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

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	12
Dann	Benign	0.86
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.41	T;T;T
MetaRNN	Benign	0.0022	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.25	T
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	T
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

Other links and lift over

dbSNP: rs35019869; hg19: chr1-26131638; COSMIC: COSV99052734;