rs139020143

Variant names:

• chr1-25808771-G-A
• rs139020143
• NM_020451.3:c.729G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_020451.3(SELENON):​c.729G>A​(p.Pro243Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00058 in 1,613,778 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00051 (3 hom.)
• Consequence: SELENON NM_020451.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: -2.95
• Publications: 0 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, STRONG Submitted by: PanelApp Australia, G2P, Ambry Genetics
• 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=-0.86).
• BP6: Variant 1-25808771-G-A is Benign according to our data. Variant chr1-25808771-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 261284.
• BP7: Synonymous conserved (PhyloP=-2.95 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00128 (195/152300) while in subpopulation AFR AF = 0.00318 (132/41568). AF 95% confidence interval is 0.00273. There are 1 homozygotes in GnomAd4. There are 101 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020451.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SELENON	NM_020451.3	MANE Select	c.729G>A	p.Pro243Pro	synonymous	Exon 5 of 13	NP_065184.2
	SELENON	NM_206926.2		c.627G>A	p.Pro209Pro	synonymous	Exon 4 of 12	NP_996809.1	Q9NZV5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SELENON	ENST00000361547.7	TSL:1 MANE Select	c.729G>A	p.Pro243Pro	synonymous	Exon 5 of 13	ENSP00000355141.2	Q9NZV5-1
	SELENON	ENST00000374315.1	TSL:5	c.627G>A	p.Pro209Pro	synonymous	Exon 4 of 12	ENSP00000363434.1	Q9NZV5-2
	SELENON	ENST00000354177.9	TSL:5	c.627G>A	p.Pro209Pro	synonymous	Exon 4 of 12	ENSP00000346109.5	H9KV50

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 188 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00302

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00894

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000723 AC: 180 AN: 249002 AF XY: 0.000702

Gnomad AFR exome AF: 0.00214

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.00815

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000355

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000507 AC: 741 AN: 1461478 Hom.: 3 Cov.: 32 AF XY: 0.000505 AC XY: 367 AN XY: 727044

African (AFR) AF: 0.00284 AC: 95 AN: 33478

American (AMR) AF: 0.000380 AC: 17 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00987 AC: 258 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.0000753 AC: 4 AN: 53116

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.000274 AC: 305 AN: 1111932

Other (OTH) AF: 0.000911 AC: 55 AN: 60378

GnomAD4 genome AF: 0.00128 AC: 195 AN: 152300 Hom.: 1 Cov.: 33 AF XY: 0.00136 AC XY: 101 AN XY: 74458

African (AFR) AF: 0.00318 AC: 132 AN: 41568

American (AMR) AF: 0.000327 AC: 5 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00894 AC: 31 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68012

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00143 Hom.: 1

Bravo AF: 0.00143

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	1	Eichsfeld type congenital muscular dystrophy (1)
-	-	1	not specified (1)
-	-	1	SELENON-related disorder (1)
-	1	-	SEPN1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.13
DANN	Benign	0.77
PhyloP100		-2.9
Mutation Taster		=100/0	polymorphism

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: rs139020143; hg19: chr1-26135262; COSMIC: COSV62524978; COSMIC: COSV62524978;