rs11247735

Variant names:

• chr1-25804968-G-A
• rs11247735
• NM_020451.3:c.404-174G>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• rigid spine muscular dystrophy 1

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics, G2P
• SELENON-related myopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• congenital myopathy 4A, autosomal dominant

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• congenital fiber-type disproportion myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• desmin-related myopathy with Mallory body-like inclusions

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• rigid spine syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
SELENON	NM_020451.3	c.404-174G>A		intron_variant	Intron 3 of 12	ENST00000361547.7	NP_065184.2
SELENON	NM_206926.2	c.302-174G>A		intron_variant	Intron 2 of 11		NP_996809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SELENON	ENST00000361547.7	c.404-174G>A		intron_variant	Intron 3 of 12	1	NM_020451.3	ENSP00000355141.2
SELENON	ENST00000374315.1	c.302-174G>A		intron_variant	Intron 2 of 11	5		ENSP00000363434.1
SELENON	ENST00000354177.9	c.302-174G>A		intron_variant	Intron 2 of 11	5		ENSP00000346109.5
SELENON	ENST00000494537.2	n.302-174G>A		intron_variant	Intron 2 of 12	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

African (AFR) AF: 0.492 AC: 20372 AN: 41388

American (AMR) AF: 0.630 AC: 9624 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.413 AC: 1432 AN: 3470

East Asian (EAS) AF: 0.611 AC: 3152 AN: 5156

South Asian (SAS) AF: 0.684 AC: 3293 AN: 4812

European-Finnish (FIN) AF: 0.462 AC: 4864 AN: 10518

Middle Eastern (MID) AF: 0.445 AC: 130 AN: 292

European-Non Finnish (NFE) AF: 0.483 AC: 32769 AN: 67908

Other (OTH) AF: 0.514 AC: 1083 AN: 2108

Alfa AF: 0.494 Hom.: 24068

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

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.018
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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