rs1371866855

chr1-25800240-G-Cchr1-25800240-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020451.3(SELENON):c.10G>C(p.Ala4Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 846,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A4S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000041 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: SELENON NM_020451.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.79

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1456689).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SELENON	NM_020451.3	c.10G>C	p.Ala4Pro	missense_variant	1/13	ENST00000361547.7
SELENON	NM_206926.2	c.10G>C	p.Ala4Pro	missense_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SELENON	ENST00000361547.7	c.10G>C	p.Ala4Pro	missense_variant	1/13	1	NM_020451.3
SELENON	ENST00000374315.1	c.10G>C	p.Ala4Pro	missense_variant	1/12	5		P1
SELENON	ENST00000354177.9	c.10G>C	p.Ala4Pro	missense_variant	1/12	5
SELENON	ENST00000494537.2	c.10G>C	p.Ala4Pro	missense_variant, NMD_transcript_variant	1/13	3

Frequencies

GnomAD3 genomes AF: 0.0000414 AC: 6 AN: 145074 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00119

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000570 AC: 4 AN: 701222 Hom.: 0 Cov.: 9 AF XY: 0.00000614 AC XY: 2 AN XY: 325624

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000335

Gnomad4 SAS exome AF: 0.0000689

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000156

Gnomad4 OTH exome AF: 0.0000435

GnomAD4 genome AF: 0.0000413 AC: 6 AN: 145130 Hom.: 0 Cov.: 30 AF XY: 0.0000283 AC XY: 2 AN XY: 70592

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00119

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Eichsfeld type congenital muscular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 08, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SELENON protein function. ClinVar contains an entry for this variant (Variation ID: 663642). This variant has not been reported in the literature in individuals affected with SELENON-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 4 of the SELENON protein (p.Ala4Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	11
Dann	Benign	0.97
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.31	T;T;T
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.62	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.010	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.039	D;D;D
Sift4G	Uncertain	0.027	D;D;D
Polyphen		0.53, 0.43	.;P;B
Vest4		0.065
MutPred		0.22		Loss of MoRF binding (P = 0.0274);Loss of MoRF binding (P = 0.0274);Loss of MoRF binding (P = 0.0274);
MVP		0.75
MPC		0.30
ClinPred		0.35	T
GERP RS		-0.16
Varity_R		0.13

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: rs1371866855; hg19: chr1-26126731;