rs11247735

Positions:

• chr1-25804968-G-A
• chr1-25804968-G-C
• chr1-25804968-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_020451.3(SELENON):​c.404-174G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.508 in 151,838 control chromosomes in the GnomAD database, including 19,905 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.51 (19905 hom., cov: 31)
• Consequence: SELENON NM_020451.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0180

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-25804968-G-A is Benign according to our data. Variant chr1-25804968-G-A is described in ClinVar as [Benign]. Clinvar id is 669829.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.665 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SELENON	NM_020451.3	c.404-174G>A		intron_variant		ENST00000361547.7	NP_065184.2
SELENON	NM_206926.2	c.302-174G>A		intron_variant			NP_996809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SELENON	ENST00000361547.7	c.404-174G>A		intron_variant		1	NM_020451.3	ENSP00000355141.2
SELENON	ENST00000374315.1	c.302-174G>A		intron_variant		5		ENSP00000363434.1
SELENON	ENST00000354177.9	c.302-174G>A		intron_variant		5		ENSP00000346109.5
SELENON	ENST00000494537.2	n.302-174G>A		intron_variant		3		ENSP00000508308.1

Frequencies

GnomAD3 genomes AF: 0.508 AC: 77135 AN: 151720 Hom.: 19881 Cov.: 31

Gnomad AFR AF: 0.492

Gnomad AMI AF: 0.535

Gnomad AMR AF: 0.629

Gnomad ASJ AF: 0.413

Gnomad EAS AF: 0.612

Gnomad SAS AF: 0.686

Gnomad FIN AF: 0.462

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.482

Gnomad OTH AF: 0.512

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.508 AC: 77205 AN: 151838 Hom.: 19905 Cov.: 31 AF XY: 0.514 AC XY: 38101 AN XY: 74162

Gnomad4 AFR AF: 0.492

Gnomad4 AMR AF: 0.630

Gnomad4 ASJ AF: 0.413

Gnomad4 EAS AF: 0.611

Gnomad4 SAS AF: 0.684

Gnomad4 FIN AF: 0.462

Gnomad4 NFE AF: 0.483

Gnomad4 OTH AF: 0.514

Alfa AF: 0.490 Hom.: 18039

Bravo AF: 0.514

Asia WGS AF: 0.654 AC: 2277 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 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	-0.85
CADD	Benign	2.6
DANN	Benign	0.37

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: rs11247735; hg19: chr1-26131459; COSMIC: COSV62524936;