rs561190371
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong
The NM_015046.7(SETX):āc.2755G>Cā(p.Val919Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000216 in 1,613,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_015046.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000105 AC: 16AN: 152204Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000479 AC: 12AN: 250628Hom.: 0 AF XY: 0.0000738 AC XY: 10AN XY: 135468
GnomAD4 exome AF: 0.000227 AC: 332AN: 1461284Hom.: 0 Cov.: 36 AF XY: 0.000212 AC XY: 154AN XY: 726926
GnomAD4 genome AF: 0.000105 AC: 16AN: 152204Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8AN XY: 74352
ClinVar
Submissions by phenotype
Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2;C1865409:Amyotrophic lateral sclerosis type 4 Benign:1Other:1
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Variant reported in multiple, related GenomeConnect-Invitae Patient Insights Network participants. Variant was reported by multiple clinical laboraties in this family and interpreted as Uncertain significance by all laboratories. The variant was reported most recently on 09/25/2017 by Invitae and reported on 04/30/2014 by Lab Athena. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details for both related participants are available under supporting information. -
not specified Uncertain:1
Variant summary: SETX c.2755G>C (p.Val919Leu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 250628 control chromosomes, predominantly at a frequency of 0.00011 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in SETX causing Amyotrophic Lateral Sclerosis Type 4, allowing no conclusion about variant significance. c.2755G>C has been reported in the literature in heterozygous individuals affected with Amyotrophic Lateral Sclerosis, without strong evidence of causality (examples: Kenna_2013, McCann_2021). These data do not allow any conclusion about variant association with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23881933, 32409511). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=4) or benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Inborn genetic diseases Uncertain:1
Unlikely to be causative of SETX-related juvenile amyotrophic lateral sclerosis (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Amyotrophic lateral sclerosis type 4 Uncertain:1
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not provided Uncertain:1
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) Computational tools predict that this variant is not damaging. -
Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at