rs754298562
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_001164507.2(NEB):āc.10127A>Gā(p.Tyr3376Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000744 in 1,613,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.000026 ( 0 hom., cov: 32)
Exomes š: 0.0000055 ( 0 hom. )
Consequence
NEB
NM_001164507.2 missense
NM_001164507.2 missense
Scores
5
9
4
Clinical Significance
Conservation
PhyloP100: 6.13
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 Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.816
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEB | NM_001164507.2 | c.10127A>G | p.Tyr3376Cys | missense_variant | 69/182 | ENST00000427231.7 | |
NEB | NM_001164508.2 | c.10127A>G | p.Tyr3376Cys | missense_variant | 69/182 | ENST00000397345.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEB | ENST00000397345.8 | c.10127A>G | p.Tyr3376Cys | missense_variant | 69/182 | 5 | NM_001164508.2 | P5 | |
NEB | ENST00000427231.7 | c.10127A>G | p.Tyr3376Cys | missense_variant | 69/182 | 5 | NM_001164507.2 | A2 | |
NEB | ENST00000409198.5 | c.9398A>G | p.Tyr3133Cys | missense_variant | 66/150 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152220Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000121 AC: 3AN: 248878Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 135026
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GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461618Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727078
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152220Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74366
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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 | Aug 15, 2022 | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 3376 of the NEB protein (p.Tyr3376Cys). This variant is present in population databases (rs754298562, gnomAD 0.01%). 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: 533962). 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. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;.;.
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
H;.;.;.;H;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;.;D;D;.;.
REVEL
Uncertain
Sift
Uncertain
D;D;.;D;D;.;.
Sift4G
Uncertain
D;D;D;D;D;D;D
Polyphen
1.0
.;.;.;.;D;.;.
Vest4
MutPred
Loss of disorder (P = 0.0817);.;.;.;Loss of disorder (P = 0.0817);.;.;
MVP
MPC
0.38
ClinPred
D
GERP RS
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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