rs886041390

chr16-31191431-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_004960.4(FUS):c.1574C>T(p.Pro525Leu) variant causes a missense change. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P525A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FUS NM_004960.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.47

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 16 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 chr16-31191430-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 2046744.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915
• PP5: Variant 16-31191431-C-T is Pathogenic according to our data. Variant chr16-31191431-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 280110.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-31191431-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FUS	NM_004960.4	c.1574C>T	p.Pro525Leu	missense_variant	15/15	ENST00000254108.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FUS	ENST00000254108.12	c.1574C>T	p.Pro525Leu	missense_variant	15/15	1	NM_004960.4	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251428 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135898

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	FUS: PM1, PM2, PM5, PM6, PS3:Moderate, PS4:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2019	Published in vitro functional studies demonstrate mislocalization of the FUS protein product in the cytoplasm instead of the nucleus (Dormann et al., 2010; Coady et al., 2015); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 24899262, 19450904, 20668261, 21280085, 25173930, 21604077, 20606625, 21949354, 24280224, 25625564, 22778397, 20579074, 22980027, 21907581, 26251528, 25792726, 20668259, 27123482, 25912081, 26298469, 23881933, 21881207, 23056579, 30808650, 19251627, 30684766, 30455313, 31682085, 31630970, 32579787, 32307925, 33580145, 32479602) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 28, 2014	- -

FUS-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2023

The FUS c.1574C>T variant is predicted to result in the amino acid substitution p.Pro525Leu. This variant has been repeatedly reported to be causative for amyotrophic lateral sclerosis (e.g., Kwiatkowski et al. 2009. PubMed ID: 19251627; Mackenzie et al. 2011. PubMed ID: 21604077). Of note, the Pro525 residue is located in the final 13 amino acid residues of the FUS protein, a region highly conserved among species. A significant number of FUS causative variants that have been reported in patients with ALS are located in the final 13 amino acids, between amino acid 514 and 526 (Kwiatkowski et al. 2009. PubMed ID: 19251627; Lagier-Tourenne and Cleveland. 2009. PubMed ID: 19303844). This variant has been interpreted as pathogenic by multiple submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/280110). Taken together, this variant is interpreted as pathogenic. -

Juvenile amyotrophic lateral sclerosis Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University

Mar 31, 2020

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 03, 2022

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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 280110). This missense change has been observed in individual(s) with juvenile ALS and amyotrophic lateral sclerosis (ALS) (PMID: 19251627, 20579074, 21604077, 21907581, 22980027, 27123482). In at least one individual the variant was observed to be de novo. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 525 of the FUS protein (p.Pro525Leu). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FUS function (PMID: 20606625, 21280085, 24899262, 25173930, 25625564, 26251528). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.086
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.4	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.5	D;D;D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.38	B;P;.
Vest4		0.73
MutPred		0.75		Loss of glycosylation at P525 (P = 0.0444);.;.;
MVP		0.98
MPC		2.1
ClinPred		0.99	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.81
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs886041390; hg19: chr16-31202752;