rs886038435
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1
The NM_001164508.2(NEB):c.13534G>A(p.Ala4512Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.058 ( 0 hom., cov: 0)
Exomes 𝑓: 0.032 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
NEB
NM_001164508.2 missense
NM_001164508.2 missense
Scores
3
13
Clinical Significance
Conservation
PhyloP100: -5.64
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 Benign. Variant got -9 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.0038007498).
BP6
Variant 2-151600696-C-T is Benign according to our data. Variant chr2-151600696-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 257734.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=1}.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0584 (9/154) while in subpopulation NFE AF= 0.0921 (7/76). AF 95% confidence interval is 0.0432. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NEB | NM_001164507.2 | c.13534G>A | p.Ala4512Thr | missense_variant | 89/182 | ENST00000427231.7 | NP_001157979.2 | |
NEB | NM_001164508.2 | c.13534G>A | p.Ala4512Thr | missense_variant | 89/182 | ENST00000397345.8 | NP_001157980.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NEB | ENST00000397345.8 | c.13534G>A | p.Ala4512Thr | missense_variant | 89/182 | 5 | NM_001164508.2 | ENSP00000380505 | P5 | |
NEB | ENST00000427231.7 | c.13534G>A | p.Ala4512Thr | missense_variant | 89/182 | 5 | NM_001164507.2 | ENSP00000416578 | A2 | |
NEB | ENST00000409198.5 | c.11601+9113G>A | intron_variant | 5 | ENSP00000386259 |
Frequencies
GnomAD3 genomes AF: 0.0577 AC: 9AN: 156Hom.: 0 Cov.: 0
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0324 AC: 756AN: 23342Hom.: 0 Cov.: 0 AF XY: 0.0333 AC XY: 431AN XY: 12940
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Data not reliable, filtered out with message: AS_VQSR
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GnomAD4 genome AF: 0.0584 AC: 9AN: 154Hom.: 0 Cov.: 0 AF XY: 0.0610 AC XY: 5AN XY: 82
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Nemaline myopathy 2 Uncertain:1Benign:1
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | May 30, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 29, 2017 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 14, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
.;T;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D;D;.;.
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
N;N;N;N
PROVEAN
Benign
N;.;N;.;.
REVEL
Benign
Sift
Uncertain
D;.;D;.;.
Sift4G
Uncertain
D;D;D;D;D
Vest4
MutPred
Gain of phosphorylation at A4512 (P = 0.053);Gain of phosphorylation at A4512 (P = 0.053);Gain of phosphorylation at A4512 (P = 0.053);Gain of phosphorylation at A4512 (P = 0.053);Gain of phosphorylation at A4512 (P = 0.053);
MPC
0.22
ClinPred
T
GERP RS
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at