1-25800231-A-T

Position:

• chr1-25800231-A-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PM2

The NM_020451.3(SELENON):​c.1A>T​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000161 in 622,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: SELENON NM_020451.3 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.59

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_020451.3 (SELENON) was described as [Likely_pathogenic] in ClinVar as 4491
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SELENON	NM_020451.3	c.1A>T	p.Met1?	start_lost	1/13	ENST00000361547.7
SELENON	NM_206926.2	c.1A>T	p.Met1?	start_lost	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SELENON	ENST00000361547.7	c.1A>T	p.Met1?	start_lost	1/13	1	NM_020451.3
SELENON	ENST00000374315.1	c.1A>T	p.Met1?	start_lost	1/12	5		P1
SELENON	ENST00000354177.9	c.1A>T	p.Met1?	start_lost	1/12	5
SELENON	ENST00000494537.2	c.1A>T	p.Met1?	start_lost, NMD_transcript_variant	1/13	3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000161 AC: 1 AN: 622656 Hom.: 0 Cov.: 8 AF XY: 0.00000345 AC XY: 1 AN XY: 289794

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000176

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	12
DANN	Benign	0.88
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.057	N
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	-0.23	T
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Benign	-0.18	N;N;N
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.064, 0.10	.;B;B
Vest4		0.41
MutPred		1.0		Loss of MoRF binding (P = 0.1618);Loss of MoRF binding (P = 0.1618);Loss of MoRF binding (P = 0.1618);
MVP		0.78
ClinPred		0.98	D
GERP RS		2.0
Varity_R		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs121908184; hg19: chr1-26126722;