chr16-31191418-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP5

The NM_004960.4(FUS):​c.1561C>A​(p.Arg521Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in Lovd as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R521C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

FUS
NM_004960.4 missense

Scores

6
9
4

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.83
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1
In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain 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 chr16-31191418-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 16224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP5
Variant 16-31191418-C-A is Pathogenic according to our data. Variant chr16-31191418-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FUSNM_004960.4 linkuse as main transcriptc.1561C>A p.Arg521Ser missense_variant 15/15 ENST00000254108.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FUSENST00000254108.12 linkuse as main transcriptc.1561C>A p.Arg521Ser missense_variant 15/151 NM_004960.4 P4P35637-1

Frequencies

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.48
D
BayesDel_noAF
Pathogenic
0.44
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.78
D;.;T
Eigen
Benign
-0.24
Eigen_PC
Benign
-0.17
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Benign
0.85
D;D;T
M_CAP
Pathogenic
0.33
D
MetaRNN
Uncertain
0.55
D;D;D
MetaSVM
Uncertain
0.44
D
MutationAssessor
Uncertain
2.2
M;.;.
MutationTaster
Benign
0.99
D;D;D
PrimateAI
Uncertain
0.57
T
PROVEAN
Uncertain
-3.0
D;D;D
REVEL
Pathogenic
0.67
Sift
Pathogenic
0.0
D;D;D
Sift4G
Uncertain
0.031
D;D;D
Polyphen
0.093
B;B;.
Vest4
0.47
MutPred
0.73
Gain of phosphorylation at R521 (P = 4e-04);.;.;
MVP
1.0
MPC
2.0
ClinPred
0.98
D
GERP RS
0.20
RBP_binding_hub_radar
1.1
RBP_regulation_power_radar
2.4
Varity_R
0.95
gMVP
0.91

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.26
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.26
Position offset: -19

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: rs121909668; hg19: chr16-31202739; API