chr1-25809753-G-A

Variant names:

• chr1-25809753-G-A
• rs121908188
• NM_020451.3:c.943G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM5 PP3_Moderate PP5_Very_Strong

The NM_020451.3(SELENON):​c.943G>A​(p.Gly315Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000509 in 1,613,918 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000238454: Protein levels tested from fibroblast cells of an affected patient showed reduced activity of the protein (Maiti et al. 2009, PMID:19067361).; SCV000967683: analysis using fibroblast cells of an affected patient showed an impact on protein activity (Maiti 2009).; SCV002507069: "In vitro functional studies provide some evidence that the variant may slightly impact protein function." PMID:19067361; SCV005397302: "Protein expression studies found that this variant along with a second missense variant led to an approximate 80% decrease in protein expression in patient fibroblasts." PMID:19067361; SCV005849071: "functional studies provide supportive evidence that the variant has a damaging effect on the gene or gene product." PMID 19067361; SCV000238453: Protein levels tested from fibroblast cells of an affected patient showed reduced activity of the protein (Maiti et al. 2009, PMID:19067361).; SCV000809113: PS3_supporting; SCV000914403: Cultured fibroblasts from an individual compound heterozygous for the p.Gly315Ser variant was found to have enzyme activity 20% of wild type but mRNA levels were found to be near normal (Maiti et al. 2009).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G315R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00053 (1 hom.)
• Consequence: SELENON NM_020451.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:26 O:1
• Conservation: PhyloP100: 8.12
• Publications: 20 publications found

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 Gene-Disease associations (from GenCC):

• rigid spine muscular dystrophy 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Ambry Genetics
• SELENON-related myopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• congenital myopathy 4A, autosomal dominant

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• congenital fiber-type disproportion myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• desmin-related myopathy with Mallory body-like inclusions

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• rigid spine syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000238454: Protein levels tested from fibroblast cells of an affected patient showed reduced activity of the protein (Maiti et al. 2009, PMID: 19067361).; SCV000967683: analysis using fibroblast cells of an affected patient showed an impact on protein activity (Maiti 2009).; SCV002507069: "In vitro functional studies provide some evidence that the variant may slightly impact protein function." PMID:19067361; SCV005397302: "Protein expression studies found that this variant along with a second missense variant led to an approximate 80% decrease in protein expression in patient fibroblasts." PMID:19067361; SCV005849071: "functional studies provide supportive evidence that the variant has a damaging effect on the gene or gene product." PMID 19067361; SCV000238453: Protein levels tested from fibroblast cells of an affected patient showed reduced activity of the protein (Maiti et al. 2009, PMID: 19067361).; SCV000809113: PS3_supporting; SCV000914403: Cultured fibroblasts from an individual compound heterozygous for the p.Gly315Ser variant was found to have enzyme activity 20% of wild type but mRNA levels were found to be near normal (Maiti et al. 2009).
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-25809753-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 661692.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855
• PP5: Variant 1-25809753-G-A is Pathogenic according to our data. Variant chr1-25809753-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020451.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SELENON	NM_020451.3	MANE Select	c.943G>A	p.Gly315Ser	missense	Exon 7 of 13	NP_065184.2
	SELENON	NM_206926.2		c.841G>A	p.Gly281Ser	missense	Exon 6 of 12	NP_996809.1	Q9NZV5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SELENON	ENST00000361547.7	TSL:1 MANE Select	c.943G>A	p.Gly315Ser	missense	Exon 7 of 13	ENSP00000355141.2	Q9NZV5-1
	SELENON	ENST00000374315.1	TSL:5	c.841G>A	p.Gly281Ser	missense	Exon 6 of 12	ENSP00000363434.1	Q9NZV5-2
	SELENON	ENST00000354177.9	TSL:5	c.772G>A	p.Gly258Ser	missense	Exon 6 of 12	ENSP00000346109.5	H9KV50

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152104 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000176 AC: 44 AN: 249510 AF XY: 0.000199

Gnomad AFR exome AF: 0.0000645

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000930

Gnomad NFE exome AF: 0.000362

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000532 AC: 777 AN: 1461814 Hom.: 1 Cov.: 32 AF XY: 0.000490 AC XY: 356 AN XY: 727218

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.000169 AC: 9 AN: 53344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000679 AC: 755 AN: 1112010

Other (OTH) AF: 0.000166 AC: 10 AN: 60394

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152104 Hom.: 0 Cov.: 33 AF XY: 0.000229 AC XY: 17 AN XY: 74288

African (AFR) AF: 0.000169 AC: 7 AN: 41408

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000529 AC: 36 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000438 Hom.: 1

Bravo AF: 0.000287

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000233 AC: 1

ESP6500EA AF: 0.000588 AC: 5

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.000654

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
12	-	-	Eichsfeld type congenital muscular dystrophy (12)
6	-	-	not provided (6)
3	-	-	Congenital myopathy with fiber type disproportion (4)
2	-	-	Eichsfeld type congenital muscular dystrophy;C0546264:Congenital myopathy with fiber type disproportion (2)
1	-	-	Eichsfeld type congenital muscular dystrophy;CN178536:Congenital myopathy 4A, autosomal dominant (1)
1	-	-	SELENON-related myopathy (1)
1	-	-	SEPN1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		8.1
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MVP		0.97
MPC		0.86
ClinPred		0.42	T
GERP RS		4.8
Varity_R		0.53
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121908188; hg19: chr1-26136244;