16-31191419-G-T

Variant names:

• chr16-31191419-G-T
• rs121909671
• NM_004960.4:c.1562G>T

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.1562G>T​(p.Arg521Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely 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/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.31

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 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 chr16-31191418-C-T is described in Lovd as [Pathogenic].
• PP5: Variant 16-31191419-G-T is Pathogenic according to our data. Variant chr16-31191419-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 873232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-31191419-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FUS	NM_004960.4	c.1562G>T	p.Arg521Leu	missense_variant	Exon 15 of 15	ENST00000254108.12	NP_004951.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FUS	ENST00000254108.12	c.1562G>T	p.Arg521Leu	missense_variant	Exon 15 of 15	1	NM_004960.4	ENSP00000254108.8

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyotrophic lateral sclerosis type 6 Pathogenic:2

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant c.1562G>T (p.Arg521Leu) in FUS gene has been reported in literatures with Amyotrophic lateral sclerosis(Swetha RG et.al.,2017). Experimental studies have shown that this variant affects FUS function (Armstrong GA et.al.,2013).This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The p.Arg521Leu variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Arg at position 521 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -

Mar 31, 2020

Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

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

Sep 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with amyotrophic lateral sclerosis (PMID: 20577002, 20668259, 22340366, 26500017, 28430856). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 873232). 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 C15"). This variant disrupts the p.Arg521 amino acid residue in FUS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20577002, 20668259, 22340366, 26500017, 28430856). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 521 of the FUS protein (p.Arg521Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.086
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Uncertain	0.69	D;D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.2	M;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-4.0	D;D;D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.018	D;D;D
Polyphen		0.049	B;B;.
Vest4		0.56
MutPred		0.67		Loss of MoRF binding (P = 0.0023);.;.;
MVP		1.0
MPC		2.1
ClinPred		0.99	D
GERP RS		1.8
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2
Varity_R		0.92
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs121909671; hg19: chr16-31202740;