rs917645712
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001164507.2(NEB):c.2923G>A(p.Ala975Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,612,732 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
NEB
NM_001164507.2 missense
NM_001164507.2 missense
Scores
6
4
8
Clinical Significance
Conservation
PhyloP100: 6.04
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 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEB | NM_001164507.2 | c.2923G>A | p.Ala975Thr | missense_variant | 29/182 | ENST00000427231.7 | |
NEB | NM_001164508.2 | c.2923G>A | p.Ala975Thr | missense_variant | 29/182 | ENST00000397345.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEB | ENST00000397345.8 | c.2923G>A | p.Ala975Thr | missense_variant | 29/182 | 5 | NM_001164508.2 | P5 | |
NEB | ENST00000427231.7 | c.2923G>A | p.Ala975Thr | missense_variant | 29/182 | 5 | NM_001164507.2 | A2 | |
NEB | ENST00000409198.5 | c.2923G>A | p.Ala975Thr | missense_variant | 29/150 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152164Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460568Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 726512
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152164Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74336
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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. | Feb 11, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2021 | This sequence change replaces alanine with threonine at codon 975 of the NEB protein (p.Ala975Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with NEB-related conditions. 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
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Pathogenic
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;.;.
M_CAP
Benign
T
MetaRNN
Uncertain
D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;M;.;M;M;M;M
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;.;N;N;.;.
REVEL
Benign
Sift
Pathogenic
D;T;.;T;D;.;.
Sift4G
Uncertain
D;D;D;D;D;D;D
Polyphen
1.0
.;.;.;.;D;.;.
Vest4
MutPred
Gain of phosphorylation at A975 (P = 0.043);Gain of phosphorylation at A975 (P = 0.043);Gain of phosphorylation at A975 (P = 0.043);Gain of phosphorylation at A975 (P = 0.043);Gain of phosphorylation at A975 (P = 0.043);Gain of phosphorylation at A975 (P = 0.043);Gain of phosphorylation at A975 (P = 0.043);
MVP
MPC
0.34
ClinPred
D
GERP RS
Varity_R
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