rs121909668

chr16-31191418-C-Achr16-31191418-C-Gchr16-31191418-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.83

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]

ACMG classification

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
FUS	NM_004960.4	c.1561C>A	p.Arg521Ser	missense_variant	15/15	ENST00000254108.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FUS	ENST00000254108.12	c.1561C>A	p.Arg521Ser	missense_variant	15/15	1	NM_004960.4	P4

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

Other links and lift over

dbSNP: rs121909668; hg19: chr16-31202739;