rs115986826
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3BS2_Supporting
The NM_001164507.2(NEB):āc.3986A>Cā(p.Asp1329Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00121 in 1,613,034 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D1329D) has been classified as Uncertain significance.
Frequency
Consequence
NM_001164507.2 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEB | NM_001164507.2 | c.3986A>C | p.Asp1329Ala | missense_variant, splice_region_variant | 36/182 | ENST00000427231.7 | |
NEB | NM_001164508.2 | c.3986A>C | p.Asp1329Ala | missense_variant, splice_region_variant | 36/182 | ENST00000397345.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEB | ENST00000397345.8 | c.3986A>C | p.Asp1329Ala | missense_variant, splice_region_variant | 36/182 | 5 | NM_001164508.2 | P5 | |
NEB | ENST00000427231.7 | c.3986A>C | p.Asp1329Ala | missense_variant, splice_region_variant | 36/182 | 5 | NM_001164507.2 | A2 | |
NEB | ENST00000409198.5 | c.3986A>C | p.Asp1329Ala | missense_variant, splice_region_variant | 36/150 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000919 AC: 140AN: 152260Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000967 AC: 241AN: 249242Hom.: 0 AF XY: 0.000924 AC XY: 125AN XY: 135210
GnomAD4 exome AF: 0.00124 AC: 1808AN: 1460656Hom.: 3 Cov.: 29 AF XY: 0.00121 AC XY: 880AN XY: 726684
GnomAD4 genome ? AF: 0.000919 AC: 140AN: 152378Hom.: 0 Cov.: 31 AF XY: 0.000872 AC XY: 65AN XY: 74522
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 22, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 22, 2020 | This variant is associated with the following publications: (PMID: 30091983) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 17, 2021 | - - |
Nemaline myopathy 2 Uncertain:2Other:1
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpreted as Uncertain significance and reported on 09-14-2018 by Lab or GTR ID 239772. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 17, 2022 | This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 1329 of the NEB protein (p.Asp1329Ala). This variant is present in population databases (rs115986826, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of nemaline myopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 331513). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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. - |
Actin accumulation myopathy Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Uncertain significance and reported on 01-11-2021 by Lab Invitae. 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 are available under supporting information. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at