rs267606831
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_004960.4(FUS):c.1520G>A(p.Gly507Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Consequence
FUS
NM_004960.4 missense
NM_004960.4 missense
Scores
11
3
5
Clinical Significance
Conservation
PhyloP100: 6.19
Genes affected
FUS (HGNC:4010): (FUS RNA binding protein) This gene encodes a multifunctional protein component of the heterogeneous nuclear ribonucleoprotein (hnRNP) complex. The hnRNP complex is involved in pre-mRNA splicing and the export of fully processed mRNA to the cytoplasm. This protein belongs to the FET family of RNA-binding proteins which have been implicated in cellular processes that include regulation of gene expression, maintenance of genomic integrity and mRNA/microRNA processing. Alternative splicing results in multiple transcript variants. Defects in this gene result in amyotrophic lateral sclerosis type 6. [provided by RefSeq, Sep 2009]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM1
In a region_of_interest Disordered (size 82) in uniprot entity FUS_HUMAN there are 35 pathogenic changes around while only 0 benign (100%) in NM_004960.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.945
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FUS | NM_004960.4 | c.1520G>A | p.Gly507Asp | missense_variant | 14/15 | ENST00000254108.12 | NP_004951.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FUS | ENST00000254108.12 | c.1520G>A | p.Gly507Asp | missense_variant | 14/15 | 1 | NM_004960.4 | ENSP00000254108.8 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
FUS-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 01, 2024 | The FUS c.1520G>A variant is predicted to result in the amino acid substitution p.Gly507Asp. This variant has previously been reported to be causative for amyotrophic lateral sclerosis (Corrado et al 2010. PubMed ID: 19861302; Morgan S et al 2017. PubMed ID: 28430856; Hewitt C et al 2010. PubMed ID: 20385912). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant also resides in a mutational hotspot for missense changes (Lattante et al. 2013. PubMed ID: 23559573). This variant is interpreted as pathogenic. - |
Amyotrophic lateral sclerosis type 6 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2010 | - - |
Amyotrophic lateral sclerosis type 6;C3539195:Tremor, hereditary essential, 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 27, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 507 of the FUS protein (p.Gly507Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 19861302, 20138404, 20385912, 28430856, 31069529). ClinVar contains an entry for this variant (Variation ID: 16226). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on FUS function (PMID: 23056579). 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
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;.;.
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
B;B;.
Vest4
MutPred
Loss of MoRF binding (P = 0.0741);.;.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at