rs4414676
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_001164507.2(NEB):c.25150+12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 1,565,382 control chromosomes in the GnomAD database, including 2,221 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.067 ( 1119 hom., cov: 32)
Exomes 𝑓: 0.0072 ( 1102 hom. )
Consequence
NEB
NM_001164507.2 intron
NM_001164507.2 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.01
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]
RIF1 (HGNC:23207): (replication timing regulatory factor 1) This gene encodes a protein that shares homology with the yeast teleomere binding protein, Rap1 interacting factor 1. This protein localizes to aberrant telomeres may be involved in DNA repair. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -20 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.71).
BP6
?
Variant 2-151491671-C-T is Benign according to our data. Variant chr2-151491671-C-T is described in ClinVar as [Benign]. Clinvar id is 226845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151491671-C-T is described in Lovd as [Likely_benign].
BA1
?
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEB | NM_001164507.2 | c.25150+12G>A | intron_variant | ENST00000427231.7 | |||
NEB | NM_001164508.2 | c.25150+12G>A | intron_variant | ENST00000397345.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEB | ENST00000397345.8 | c.25150+12G>A | intron_variant | 5 | NM_001164508.2 | P5 | |||
NEB | ENST00000427231.7 | c.25150+12G>A | intron_variant | 5 | NM_001164507.2 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0672 AC: 10216AN: 152098Hom.: 1118 Cov.: 32
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GnomAD3 exomes AF: 0.0163 AC: 3208AN: 196570Hom.: 341 AF XY: 0.0124 AC XY: 1292AN XY: 104340
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GnomAD4 exome AF: 0.00719 AC: 10159AN: 1413166Hom.: 1102 Cov.: 29 AF XY: 0.00624 AC XY: 4367AN XY: 699792
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GnomAD4 genome ? AF: 0.0672 AC: 10231AN: 152216Hom.: 1119 Cov.: 32 AF XY: 0.0641 AC XY: 4771AN XY: 74430
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ClinVar
Significance: Benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:4
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 24, 2014 | 25255+12G>A in intron 180 of NEB: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence. It has been identified in 22.3% (846/3802) of African American chromosome s from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.w ashington.edu/EVS; dbSNP rs4414676). - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 08, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 22, 2016 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 13, 2016 | - - |
Nemaline myopathy 2 Benign:2
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at