rs267606831

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

Scores

11
3
5

Clinical Significance

Uncertain significance criteria provided, single submitter P:2U:1

Conservation

PhyloP100: 6.19
Variant links:
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
FUSNM_004960.4 linkuse as main transcriptc.1520G>A p.Gly507Asp missense_variant 14/15 ENST00000254108.12 NP_004951.1 P35637-1Q6IBQ5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FUSENST00000254108.12 linkuse as main transcriptc.1520G>A p.Gly507Asp missense_variant 14/151 NM_004960.4 ENSP00000254108.8 P35637-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
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 providedclinical testingPreventionGenetics, part of Exact SciencesFeb 01, 2024The 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 providedliterature onlyOMIMApr 01, 2010- -
Amyotrophic lateral sclerosis type 6;C3539195:Tremor, hereditary essential, 4 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 27, 2024This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.51
D
BayesDel_noAF
Pathogenic
0.49
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.82
D;.;T
Eigen
Benign
-0.18
Eigen_PC
Benign
-0.080
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.84
T;T;T
M_CAP
Pathogenic
0.64
D
MetaRNN
Pathogenic
0.95
D;D;D
MetaSVM
Pathogenic
0.94
D
MutationAssessor
Benign
1.8
L;.;.
PrimateAI
Pathogenic
0.82
D
PROVEAN
Uncertain
-4.2
D;D;D
REVEL
Pathogenic
0.86
Sift
Pathogenic
0.0
D;D;D
Sift4G
Uncertain
0.010
D;D;D
Polyphen
0.13
B;B;.
Vest4
0.84
MutPred
0.83
Loss of MoRF binding (P = 0.0741);.;.;
MVP
1.0
MPC
2.4
ClinPred
0.99
D
GERP RS
4.4
RBP_binding_hub_radar
1.1
RBP_regulation_power_radar
2.2
Varity_R
0.89
gMVP
0.95

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs267606831; hg19: chr16-31202410; API