1-25808828-C-T

Position:

• chr1-25808828-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020451.3(SELENON):​c.747+39C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00225 in 1,610,098 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (15 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (17 hom.)
• Consequence: SELENON NM_020451.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.155

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 1-25808828-C-T is Benign according to our data. Variant chr1-25808828-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 261286.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00748 (1139/152280) while in subpopulation AFR AF= 0.0223 (927/41566). AF 95% confidence interval is 0.0211. There are 15 homozygotes in gnomad4. There are 552 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SELENON	NM_020451.3	c.747+39C>T		intron_variant		ENST00000361547.7	NP_065184.2
SELENON	NM_206926.2	c.645+39C>T		intron_variant			NP_996809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SELENON	ENST00000361547.7	c.747+39C>T		intron_variant		1	NM_020451.3	ENSP00000355141.2
SELENON	ENST00000374315.1	c.645+39C>T		intron_variant		5		ENSP00000363434.1
SELENON	ENST00000354177.9	c.645+39C>T		intron_variant		5		ENSP00000346109.5
SELENON	ENST00000494537.2	n.645+39C>T		intron_variant		3		ENSP00000508308.1

Frequencies

GnomAD3 genomes AF: 0.00745 AC: 1133 AN: 152162 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.0108

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00398 AC: 982 AN: 246530 Hom.: 9 AF XY: 0.00369 AC XY: 495 AN XY: 134256

Gnomad AFR exome AF: 0.0229

Gnomad AMR exome AF: 0.00166

Gnomad ASJ exome AF: 0.00471

Gnomad EAS exome AF: 0.0125

Gnomad SAS exome AF: 0.00507

Gnomad FIN exome AF: 0.00168

Gnomad NFE exome AF: 0.000928

Gnomad OTH exome AF: 0.00200

GnomAD4 exome AF: 0.00170 AC: 2478 AN: 1457818 Hom.: 17 Cov.: 31 AF XY: 0.00171 AC XY: 1244 AN XY: 725426

Gnomad4 AFR exome AF: 0.0218

Gnomad4 AMR exome AF: 0.00168

Gnomad4 ASJ exome AF: 0.00395

Gnomad4 EAS exome AF: 0.0101

Gnomad4 SAS exome AF: 0.00492

Gnomad4 FIN exome AF: 0.00184

Gnomad4 NFE exome AF: 0.000414

Gnomad4 OTH exome AF: 0.00295

GnomAD4 genome AF: 0.00748 AC: 1139 AN: 152280 Hom.: 15 Cov.: 33 AF XY: 0.00742 AC XY: 552 AN XY: 74442

Gnomad4 AFR AF: 0.0223

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.0108

Gnomad4 SAS AF: 0.00393

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00180 Hom.: 0

Bravo AF: 0.00857

Asia WGS AF: 0.0160 AC: 56 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 10, 2017	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 14, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	6.1
DANN	Benign	0.86

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: rs114458946; hg19: chr1-26135319;