rs201047535

Positions:

• chr1-25811921-G-A

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.1281+42G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00431 in 1,539,356 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0045 (13 hom.)
• Consequence: SELENON NM_020451.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.650

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=-0.8).
• BP6: Variant 1-25811921-G-A is Benign according to our data. Variant chr1-25811921-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 261273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0028 (427/152354) while in subpopulation NFE AF= 0.00497 (338/68022). AF 95% confidence interval is 0.00453. There are 1 homozygotes in gnomad4. There are 193 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SELENON	NM_020451.3	c.1281+42G>A		intron_variant		ENST00000361547.7
SELENON	NM_206926.2	c.1179+42G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SELENON	ENST00000361547.7	c.1281+42G>A		intron_variant		1	NM_020451.3
SELENON	ENST00000354177.9	c.1110+42G>A		intron_variant		5
SELENON	ENST00000374315.1	c.1179+42G>A		intron_variant		5		P1
SELENON	ENST00000494537.2	c.1179+42G>A		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00280 AC: 427 AN: 152236 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00497

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00268 AC: 399 AN: 148898 Hom.: 0 AF XY: 0.00232 AC XY: 184 AN XY: 79344

Gnomad AFR exome AF: 0.000531

Gnomad AMR exome AF: 0.00203

Gnomad ASJ exome AF: 0.000120

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000352

Gnomad FIN exome AF: 0.00340

Gnomad NFE exome AF: 0.00493

Gnomad OTH exome AF: 0.00282

GnomAD4 exome AF: 0.00448 AC: 6211 AN: 1387002 Hom.: 13 Cov.: 32 AF XY: 0.00429 AC XY: 2936 AN XY: 684740

Gnomad4 AFR exome AF: 0.000446

Gnomad4 AMR exome AF: 0.00232

Gnomad4 ASJ exome AF: 0.000199

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000380

Gnomad4 FIN exome AF: 0.00366

Gnomad4 NFE exome AF: 0.00527

Gnomad4 OTH exome AF: 0.00433

GnomAD4 genome AF: 0.00280 AC: 427 AN: 152354 Hom.: 1 Cov.: 34 AF XY: 0.00259 AC XY: 193 AN XY: 74498

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.00497

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00409 Hom.: 0

Bravo AF: 0.00288

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 29, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	14
DANN	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs201047535; hg19: chr1-26138412;