rs745886248
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_020451.3(SELENON):c.1112G>A(p.Gly371Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,456,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G371V) has been classified as Uncertain significance.
Frequency
Consequence
NM_020451.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SELENON | NM_020451.3 | c.1112G>A | p.Gly371Asp | missense_variant | 9/13 | ENST00000361547.7 | |
SELENON | NM_206926.2 | c.1010G>A | p.Gly337Asp | missense_variant | 8/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SELENON | ENST00000361547.7 | c.1112G>A | p.Gly371Asp | missense_variant | 9/13 | 1 | NM_020451.3 | ||
SELENON | ENST00000374315.1 | c.1010G>A | p.Gly337Asp | missense_variant | 8/12 | 5 | P1 | ||
SELENON | ENST00000354177.9 | c.941G>A | p.Gly314Asp | missense_variant | 8/12 | 5 | |||
SELENON | ENST00000494537.2 | c.1010G>A | p.Gly337Asp | missense_variant, NMD_transcript_variant | 8/13 | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD3 exomes AF: 0.00000428 AC: 1AN: 233754Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 127328
GnomAD4 exome AF: 0.00000343 AC: 5AN: 1456100Hom.: 0 Cov.: 36 AF XY: 0.00000276 AC XY: 2AN XY: 724006
GnomAD4 genome ? Cov.: 34
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 04, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 08, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Eichsfeld type congenital muscular dystrophy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 21, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 371 of the SELENON protein (p.Gly371Asp). 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 variant has not been reported in the literature in individuals affected with SELENON-related conditions. ClinVar contains an entry for this variant (Variation ID: 586530). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. - |
Uncertain significance, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 24, 2023 | The p.Gly371Asp variant in SELENON has not been previously reported in the literature in individuals with SELENON-RM but has been identified in 0.003% (1/32300) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs745886248). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 586530) and has been interpreted as a variant of uncertain significance by Athena Diagnostics Inc and CeGaT Praxis fuer Humangenetik Tuebingen and likely pathogenic by the Undiagnosed Diseases Network (NIH). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Gly371Asp variant is uncertain. ACMG/AMP Criteria applied: PP3, PM2_supporting (Richards 2015). - |
Eichsfeld type congenital muscular dystrophy;C0546264:Congenital myopathy with fiber type disproportion Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Undiagnosed Diseases Network, NIH | May 06, 2019 | - - |
See cases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Jul 20, 2023 | ACMG categories: PM2,BP1 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at