rs387906627

Variant names:

• chr16-31191052-C-T
• rs387906627
• NM_004960.4:c.1483C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004960.4(FUS):​c.1483C>T​(p.Arg495*) variant causes a stop gained 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FUS NM_004960.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.60

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-31191052-C-T is Pathogenic according to our data. Variant chr16-31191052-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 29707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-31191052-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FUS	NM_004960.4	c.1483C>T	p.Arg495*	stop_gained	Exon 14 of 15	ENST00000254108.12	NP_004951.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FUS	ENST00000254108.12	c.1483C>T	p.Arg495*	stop_gained	Exon 14 of 15	1	NM_004960.4	ENSP00000254108.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000805 AC: 2 AN: 248402 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135086

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyotrophic lateral sclerosis type 6 Pathogenic:2

Oct 31, 2019

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FUS c.1483C>T (p.Arg495Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. This variant has been reported in at least eight studies, in which it was identified in a heterozygous state in 14 individuals with amyotrophic lateral sclerosis (ALS) (Bosco et al. 2010; Waibel et al. 2010; Yan et al. 2010; Zou et al. 2013; Calvo et al. 2014; Kim et al 2015; King et al. 2015; Dodd et al. 2019). These cases were either familial or sporadic and the variant was presumed to have occurred de novo in two cases (Calvo et al. 2014; Kim et al 2015). Across the cases, the onset of disease was predominantly bulbar and in three familial cases, the age of disease onset ranged from 14 to 59 years (Bosco et al. 2010; Waibel et al. 2010; Yan et al. 2010). Yan et al. (2010) reported a family with multiple affected individuals and two asymptomatic carriers, aged 57 and 61 years. The p.Arg495Ter variant was absent from 622 controls (Yan et al. 2010), but is reported at a frequency of 0.000008 in the total population of the Genome Aggregation Database, but this is based on two alleles only in a region of good sequence coverage so the variant is presumed to be rare. Overexpression of variant p.Arg495Ter protein in HEK293 cells and differentiated neurons showed a predominantly cytoplasmic localization of the variant protein and an association with stress granules when under oxidative stress when compared to the wild type protein which localized to the nucleus (Bosco et al. 2010; Nakaya et al. 2018). Consistent with the overexpression studies, a marked increase in cytoplasmic localization compared to the nucleus was also observed in fibroblasts from an affected individual carrying the p.Arg495Ter variant in a heterozygous state (Lim et al. 2016). Interestingly, a transgenic p.Arg495Ter mouse line displayed no obvious signs of an ALS-like phenotype, although a higher burden of cytoplasmic p.Arg495Ter protein was noted in the motor neurons of the spinal cord (Tibshirani et al. 2015). The p.Arg495Ter variant is located within the penultimate exon and removes the nuclear localization signal from the C-terminus of the FUS protein (Bosco et al. 2010). Based on the collective evidence, the p.Arg495Ter variant is classified as pathogenic for amyotrophic lateral sclerosis. -

Aug 31, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Apr 05, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4_moderate, PM2, PM6, PP1 -

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

Jun 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 29707). This premature translational stop signal has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 20660363, 25457557, 30507891, 31682085). This variant is present in population databases (rs387906627, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Arg495*) in the FUS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FUS are known to be pathogenic (PMID: 20660363, 23217123). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Uncertain	0.21
Eigen_PC	Benign	-0.015
FATHMM_MKL	Uncertain	0.96	D
Vest4		0.64
GERP RS		-0.13
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs387906627; hg19: chr16-31202373;