10-13124053-A-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_001008212.2(OPTN):c.941A>T(p.Gln314Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,613,880 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001008212.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
OPTN | NM_001008212.2 | c.941A>T | p.Gln314Leu | missense_variant | Exon 9 of 15 | ENST00000378747.8 | NP_001008213.1 | |
OPTN | NM_001008211.1 | c.941A>T | p.Gln314Leu | missense_variant | Exon 10 of 16 | NP_001008212.1 | ||
OPTN | NM_001008213.1 | c.941A>T | p.Gln314Leu | missense_variant | Exon 10 of 16 | NP_001008214.1 | ||
OPTN | NM_021980.4 | c.941A>T | p.Gln314Leu | missense_variant | Exon 8 of 14 | NP_068815.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000722 AC: 11AN: 152270Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000151 AC: 38AN: 251158Hom.: 0 AF XY: 0.000184 AC XY: 25AN XY: 135736
GnomAD4 exome AF: 0.000108 AC: 158AN: 1461610Hom.: 1 Cov.: 30 AF XY: 0.000127 AC XY: 92AN XY: 727070
GnomAD4 genome AF: 0.0000722 AC: 11AN: 152270Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74392
ClinVar
Submissions by phenotype
not provided Uncertain:2
Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with amyotrophic lateral sclerosis. Computational tools predict that this variant is damaging. -
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Motor neuron disease Pathogenic:1
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Inborn genetic diseases Uncertain:1
The p.Q314L variant (also known as c.941A>T), located in coding exon 7 of the OPTN gene, results from an A to T substitution at nucleotide position 941. The glutamine at codon 314 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is unlikely to be causative of autosomal dominant amyotrophic lateral sclerosis; however, its contribution to the development of autosomal recessive amyotrophic lateral sclerosis is uncertain. -
Primary open angle glaucoma;C1842026:Glaucoma 1, open angle, E;C3150692:Amyotrophic lateral sclerosis type 12 Uncertain:1
This sequence change replaces glutamine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 314 of the OPTN protein (p.Gln314Leu). This variant is present in population databases (rs142812715, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of OPTN-related conditions (PMID: 21613650, 23138764, 25382069, 28089114, 31000212, 32028661, 33770234, 36133075, 36570531). ClinVar contains an entry for this variant (Variation ID: 266060). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on OPTN protein function. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at