16-31183958-C-G

Variant names:

• chr16-31183958-C-G
• rs1052352
• NM_004960.4:c.291C>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_004960.4(FUS):​c.291C>G​(p.Tyr97*) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y97Y) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FUS NM_004960.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.471
• Publications: 58 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 10 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

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.291C>G	p.Tyr97*	stop_gained	Exon 4 of 15	NP_004951.1	P35637-1
	FUS	NM_001170634.1		c.288C>G	p.Tyr96*	stop_gained	Exon 4 of 15	NP_001164105.1	P35637-2
	FUS	NM_001170937.1		c.291C>G	p.Tyr97*	stop_gained	Exon 4 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.291C>G	p.Tyr97*	stop_gained	Exon 4 of 15	ENSP00000254108.8	P35637-1
	FUS	ENST00000380244.8	TSL:1	c.288C>G	p.Tyr96*	stop_gained	Exon 4 of 15	ENSP00000369594.3	P35637-2
	FUS	ENST00000566605.5	TSL:1	n.291C>G		non_coding_transcript_exon	Exon 4 of 14	ENSP00000455073.1	H3BNZ4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 59

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Benign	0.18
Eigen_PC	Benign	-0.028
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		0.47
Vest4		0.88
GERP RS		-3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs1052352; hg19: chr16-31195279;