16-31191423-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The NM_004960.4(FUS):​c.1566G>C​(p.Arg522Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R522G) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

FUS
NM_004960.4 missense

Scores

8
7
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.774
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 compositionally_biased_region Basic and acidic residues (size 17) in uniprot entity FUS_HUMAN there are 30 pathogenic changes around while only 0 benign (100%) in NM_004960.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr16-31191421-A-G is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.867

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FUSNM_004960.4 linkc.1566G>C p.Arg522Ser missense_variant Exon 15 of 15 ENST00000254108.12 NP_004951.1 P35637-1Q6IBQ5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FUSENST00000254108.12 linkc.1566G>C p.Arg522Ser missense_variant Exon 15 of 15 1 NM_004960.4 ENSP00000254108.8 P35637-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
36
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Amyotrophic lateral sclerosis type 6;C3539195:Tremor, hereditary essential, 4 Uncertain:1
Dec 01, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals affected with FUS-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 522 of the FUS protein (p.Arg522Ser). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.30
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.81
D;.;T
Eigen
Benign
-0.087
Eigen_PC
Benign
-0.050
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Benign
0.85
D;D;T
M_CAP
Pathogenic
0.52
D
MetaRNN
Pathogenic
0.87
D;D;D
MetaSVM
Uncertain
0.74
D
MutationAssessor
Uncertain
2.3
M;.;.
PrimateAI
Uncertain
0.65
T
PROVEAN
Uncertain
-3.9
D;D;D
REVEL
Pathogenic
0.75
Sift
Pathogenic
0.0
D;D;D
Sift4G
Uncertain
0.0020
D;D;D
Polyphen
0.61
P;P;.
Vest4
0.63
MutPred
0.69
Gain of phosphorylation at R522 (P = 0.0023);.;.;
MVP
0.99
MPC
1.8
ClinPred
0.99
D
GERP RS
2.8
RBP_binding_hub_radar
1.1
RBP_regulation_power_radar
2.8
Varity_R
0.88
gMVP
0.95

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.090
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-31202744; API