rs1253831275
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong
The NM_001164507.2(NEB):c.13059+4C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000034 ( 0 hom., cov: 4)
Exomes 𝑓: 0.000025 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
NEB
NM_001164507.2 splice_donor_region, intron
NM_001164507.2 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.009948
2
Clinical Significance
Conservation
PhyloP100: -1.28
Genes affected
NEB (HGNC:7720): (nebulin) This gene encodes nebulin, a giant protein component of the cytoskeletal matrix that coexists with the thick and thin filaments within the sarcomeres of skeletal muscle. In most vertebrates, nebulin accounts for 3 to 4% of the total myofibrillar protein. The encoded protein contains approximately 30-amino acid long modules that can be classified into 7 types and other repeated modules. Protein isoform sizes vary from 600 to 800 kD due to alternative splicing that is tissue-, species-,and developmental stage-specific. Of the 183 exons in the nebulin gene, at least 43 are alternatively spliced, although exons 143 and 144 are not found in the same transcript. Of the several thousand transcript variants predicted for nebulin, the RefSeq Project has decided to create three representative RefSeq records. Mutations in this gene are associated with recessive nemaline myopathy. [provided by RefSeq, Sep 2009]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.53).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEB | NM_001164507.2 | c.13059+4C>T | splice_donor_region_variant, intron_variant | ENST00000427231.7 | |||
NEB | NM_001164508.2 | c.13059+4C>T | splice_donor_region_variant, intron_variant | ENST00000397345.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEB | ENST00000397345.8 | c.13059+4C>T | splice_donor_region_variant, intron_variant | 5 | NM_001164508.2 | P5 | |||
NEB | ENST00000427231.7 | c.13059+4C>T | splice_donor_region_variant, intron_variant | 5 | NM_001164507.2 | A2 | |||
NEB | ENST00000409198.5 | c.11601+5253C>T | intron_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 1AN: 29108Hom.: 0 Cov.: 4 FAILED QC
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GnomAD3 exomes AF: 0.0000507 AC: 2AN: 39486Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 20258
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000245 AC: 7AN: 285508Hom.: 0 Cov.: 0 AF XY: 0.00000671 AC XY: 1AN XY: 149006
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GnomAD4 genome ? Data not reliable, filtered out with message: AS_VQSR AF: 0.0000344 AC: 1AN: 29108Hom.: 0 Cov.: 4 AF XY: 0.00 AC XY: 0AN XY: 12602
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Nemaline myopathy 2 Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 11, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 18, 2022 | This variant occurs in a region of NEB (Exons 82-105) consisting of three highly homologous 8-exon repeat units (exons 82-89, exons 90-97, exons 98-105). Sequence variants in this region can be detected, but this assay cannot determine which of the three repeat units is affected, and zygosity is often ambiguous. All variants in this region are reported relative to the exon 82-89 repeat. This sequence change falls in intron 85 of the NEB gene. It does not directly change the encoded amino acid sequence of the NEB protein. It affects a nucleotide within the consensus splice site. The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has not been reported in the literature in individuals affected with NEB-related conditions. ClinVar contains an entry for this variant (Variation ID: 465471). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at