rs183272965

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_020451.3(SELENON):c.1715C>A(p.Thr572Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000212 in 1,614,204 control chromosomes in the GnomAD database, including 3 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 0.0011 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 2 hom. )

Consequence

SELENON
NM_020451.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: 6.04

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0107887685).

BP6

Variant 1-25815660-C-A is Benign according to our data. Variant chr1-25815660-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 281048.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00112 (171/152340) while in subpopulation AFR AF= 0.00399 (166/41560). AF 95% confidence interval is 0.0035. There are 1 homozygotes in gnomad4. There are 80 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SELENON	NM_020451.3 linkuse as main transcript	c.1715C>A	p.Thr572Asn	missense_variant	13/13	ENST00000361547.7
SELENON	NM_206926.2 linkuse as main transcript	c.1613C>A	p.Thr538Asn	missense_variant	12/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SELENON	ENST00000361547.7 linkuse as main transcript	c.1715C>A	p.Thr572Asn	missense_variant	13/13	1	NM_020451.3		Q9NZV5-1
SELENON	ENST00000374315.1 linkuse as main transcript	c.1613C>A	p.Thr538Asn	missense_variant	12/12	5		P1	Q9NZV5-2
SELENON	ENST00000354177.9 linkuse as main transcript	c.1544C>A	p.Thr515Asn	missense_variant	12/12	5
SELENON	ENST00000494537.2 linkuse as main transcript	c.*235C>A		3_prime_UTR_variant, NMD_transcript_variant	13/13	3

Frequencies

GnomAD3 genomes

AF:

0.00112

AC:

171

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00401

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000301

AC:

AN:

249558

Hom.:

AF XY:

0.000214

AC XY:

AN XY:

135386

show subpopulations

Gnomad AFR exome

AF:

0.00433

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000117

AC:

171

AN:

1461864

Hom.:

Cov.:

AF XY:

0.0000935

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00424

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.00112

AC:

171

AN:

152340

Hom.:

Cov.:

AF XY:

0.00107

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00399

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000295

Hom.:

Bravo

AF:

0.00140

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000397

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SELENON: BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 16, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 29, 2016	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 07, 2017

The T572N variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The T572N variant is observed in 42/9798 (0.43%) alleles from individuals of African background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. -

Eichsfeld type congenital muscular dystrophy;C0546264:Congenital myopathy with fiber type disproportion

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

SELENON-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 06, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Eichsfeld type congenital muscular dystrophy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 13, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.090

Cadd

Uncertain

Dann

Uncertain

0.99

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

D;D;D;D

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.011

T;T;T;T

MetaSVM

Uncertain

0.70

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.71

N;N;N;.

REVEL

Uncertain

0.51

Sift

Benign

0.055

T;T;T;.

Sift4G

Benign

0.10

T;T;T;D

Polyphen

1.0, 1.0

.;D;D;.

Vest4

0.60

MVP

0.99

MPC

0.88

ClinPred

0.055

GERP RS

4.8

Varity_R

0.21

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over