rs72877469

chr1-25814046-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020451.3(SELENON):c.1501-31C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00781 in 1,609,110 control chromosomes in the GnomAD database, including 643 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (360 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (283 hom.)
• Consequence: SELENON NM_020451.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.190

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 (BayesDel_noAF=-0.8).
• BP6: Variant 1-25814046-C-T is Benign according to our data. Variant chr1-25814046-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 261276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-25814046-C-T is described in Lovd as [Likely_benign]. Variant chr1-25814046-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SELENON	NM_020451.3	c.1501-31C>T		intron_variant		ENST00000361547.7
SELENON	NM_206926.2	c.1399-31C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SELENON	ENST00000361547.7	c.1501-31C>T		intron_variant		1	NM_020451.3
SELENON	ENST00000354177.9	c.1330-31C>T		intron_variant		5
SELENON	ENST00000374315.1	c.1399-31C>T		intron_variant		5		P1
SELENON	ENST00000494537.2	c.*21-31C>T		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0372 AC: 5652 AN: 152112 Hom.: 361 Cov.: 32

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.00436

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.0272

GnomAD3 exomes AF: 0.0117 AC: 2929 AN: 249342 Hom.: 139 AF XY: 0.00972 AC XY: 1315 AN XY: 135292

Gnomad AFR exome AF: 0.133

Gnomad AMR exome AF: 0.00698

Gnomad ASJ exome AF: 0.00477

Gnomad EAS exome AF: 0.0125

Gnomad SAS exome AF: 0.00516

Gnomad FIN exome AF: 0.00167

Gnomad NFE exome AF: 0.00128

Gnomad OTH exome AF: 0.00446

GnomAD4 exome AF: 0.00473 AC: 6896 AN: 1456880 Hom.: 283 Cov.: 29 AF XY: 0.00436 AC XY: 3159 AN XY: 725086

Gnomad4 AFR exome AF: 0.128

Gnomad4 AMR exome AF: 0.00742

Gnomad4 ASJ exome AF: 0.00394

Gnomad4 EAS exome AF: 0.0103

Gnomad4 SAS exome AF: 0.00521

Gnomad4 FIN exome AF: 0.00184

Gnomad4 NFE exome AF: 0.000532

Gnomad4 OTH exome AF: 0.00978

GnomAD4 genome AF: 0.0372 AC: 5664 AN: 152230 Hom.: 360 Cov.: 32 AF XY: 0.0356 AC XY: 2648 AN XY: 74418

Gnomad4 AFR AF: 0.126

Gnomad4 AMR AF: 0.0140

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.0112

Gnomad4 SAS AF: 0.00436

Gnomad4 FIN AF: 0.00169

Gnomad4 NFE AF: 0.000926

Gnomad4 OTH AF: 0.0269

Alfa AF: 0.0138 Hom.: 31

Bravo AF: 0.0424

Asia WGS AF: 0.0240 AC: 83 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 16, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	3.2
Dann	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs72877469; hg19: chr1-26140537;