16-31191419-G-T

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV004048059: Experimental studies have shown that this variant affects FUS function (Armstrong GA et.al.,2013).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R521H) 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
• Publications: 158 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: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004048059: Experimental studies have shown that this variant affects FUS function (Armstrong GA et.al.,2013).
• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 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 chr16-31191419-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 16225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 16-31191419-G-T is Pathogenic according to our data. Variant chr16-31191419-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 873232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004960.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FUS	NM_004960.4	MANE Select	c.1562G>T	p.Arg521Leu	missense	Exon 15 of 15	NP_004951.1	P35637-1
	FUS	NM_001170634.1		c.1559G>T	p.Arg520Leu	missense	Exon 15 of 15	NP_001164105.1	P35637-2
	FUS	NM_001170937.1		c.1550G>T	p.Arg517Leu	missense	Exon 15 of 15	NP_001164408.1	Q13344

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FUS	ENST00000254108.12	TSL:1 MANE Select	c.1562G>T	p.Arg521Leu	missense	Exon 15 of 15	ENSP00000254108.8	P35637-1
	FUS	ENST00000380244.8	TSL:1	c.1559G>T	p.Arg520Leu	missense	Exon 15 of 15	ENSP00000369594.3	P35637-2
	FUS	ENST00000566605.5	TSL:1	n.*735G>T		non_coding_transcript_exon	Exon 14 of 14	ENSP00000455073.1	H3BNZ4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Amyotrophic lateral sclerosis type 6 (2)
1	-	-	Amyotrophic lateral sclerosis type 6;C3539195:Tremor, hereditary essential, 4 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.086
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.3
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.018	D
Polyphen		0.049	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
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121909671; hg19: chr16-31202740;