16-31191418-C-G

Position:

• chr16-31191418-C-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_Very_Strong

The NM_004960.4(FUS):​c.1561C>G​(p.Arg521Gly) 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 ClinVar as Pathogenic (★★). 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: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• 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 Pathogenic. Variant got 14 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-G is Pathogenic according to our data. Variant chr16-31191418-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 16222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-31191418-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FUS	NM_004960.4	c.1561C>G	p.Arg521Gly	missense_variant	15/15	ENST00000254108.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FUS	ENST00000254108.12	c.1561C>G	p.Arg521Gly	missense_variant	15/15	1	NM_004960.4	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 07, 2022	This variant has not been reported in large, multi-ethnic general populations. http://gnomad.broadinstitute.org) This variant has been identified in multiple unrelated individuals with clinical features associated with this gene and appears to be associated with disease in at least one family. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant was shown to interfere with cellular localization of the protein (PMID: 20606625, 20674093, 21965298). -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	FUS: PP1:Strong, PM1, PM2, PM5, PS4:Moderate, PP4, PS3:Supporting -

FUS-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 16, 2023

The FUS c.1561C>G variant is predicted to result in the amino acid substitution p.Arg521Gly. This variant was found in several patients with amyotrophic lateral sclerosis (ALS) (Kwiatkowski et al. 2009. PubMed ID: 19251627; Millecamps et al. 2010. PubMed ID: 20577002; Yan et al. 2010. PubMed ID: 20668259; Ungaro et al. 2020. PubMed ID: 32951934). Different missense variants in the same codon (p.Arg521Ser, p.Arg521Cys, p.Arg521His, p.Arg521Leu) have been reported in individuals with ALS (e.g., Millecamps et al. 2010. PubMed ID: 20577002), suggesting that substitution of amino acid residue p.Arg521 is not tolerated. A mouse model of the p.Arg521Gly resulted in severe motor deficits phenocopying human disease (Sephton et al. 2014. PubMed ID: 25324524). The c.1561C>G variant is also interpreted as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/16222/). It has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Taken together, this variant is interpreted as pathogenic. -

Amyotrophic lateral sclerosis type 6 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 27, 2009

- -

Amyotrophic lateral sclerosis type 6;C3539195:Tremor, hereditary essential, 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 10, 2022

Experimental studies have shown that this missense change affects FUS function (PMID: 19251627, 20606625, 23577159, 24204307, 25324524). 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 16222). This missense change has been observed in individuals with amyotrophic lateral sclerosis (PMID: 19251627, 22055719; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 521 of the FUS protein (p.Arg521Gly). This variant disrupts the p.Arg521 amino acid residue in FUS. Other variant(s) that disrupt this residue have been observed in individuals with FUS-related conditions (PMID: 20577002, 20668259, 22055719, 24908169), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D;.;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	1.6	L;.;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.037	D;D;D
Polyphen		0.093	B;B;.
Vest4		0.21
MutPred		0.85		Loss of MoRF binding (P = 0.002);.;.;
MVP		1.0
MPC		2.1
ClinPred		0.98	D
GERP RS		0.20
Varity_R		0.95
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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

Other links and lift over

dbSNP: rs121909668; hg19: chr16-31202739;