16-31191423-G-C

Variant names:

• chr16-31191423-G-C
• rs138901914
• NM_004960.4:c.1566G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_004960.4(FUS):​c.1566G>C​(p.Arg522Ser) variant causes a missense 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R522G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FUS NM_004960.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.774
• Publications: 1 publications found

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]

FUS Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
• amyotrophic lateral sclerosis type 6

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• juvenile amyotrophic lateral sclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• tremor, hereditary essential, 4

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 17 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_004960.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FUS	NM_004960.4	c.1566G>C	p.Arg522Ser	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.1566G>C	p.Arg522Ser	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: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Dec 01, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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: "Possibly Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals affected with FUS-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 522 of the FUS protein (p.Arg522Ser).

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D;.;T
Eigen	Benign	-0.087
Eigen_PC	Benign	-0.050
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.85	D;D;T
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Uncertain	2.3	M;.;.
PhyloP100		0.77
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Vest4		0.63
ClinPred		0.99	D
GERP RS		2.8
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.88
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs138901914; hg19: chr16-31202744;