rs1555509569

Variant names:

• chr16-31190960-TA-T
• rs1555509569
• NM_004960.4:c.1394-2delA

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_004960.4(FUS):​c.1394-2delA variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005337434: RNA sequencing analysis confirmed that this variants results in exon 14 skipping and premature protein termination (Figure 1, Yang et al. 2023. PubMed ID: 36511129). Additional immunofluorescence studies have found that this variant leads to abnormal protein localization in the cytoplasm, likely due to the loss of the C-terminal nuclear localization signal (Figure 2, same study).".

• Frequency: Genomes: not found (cov: 32)
• Consequence: FUS NM_004960.4 splice_acceptor, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.10
• Publications: 2 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 22 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV005337434: RNA sequencing analysis confirmed that this variants results in exon 14 skipping and premature protein termination (Figure 1, Yang et al. 2023. PubMed ID: 36511129). Additional immunofluorescence studies have found that this variant leads to abnormal protein localization in the cytoplasm, likely due to the loss of the C-terminal nuclear localization signal (Figure 2, same study).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-31190960-TA-T is Pathogenic according to our data. Variant chr16-31190960-TA-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 447355.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.1394-2delA		splice_acceptor intron	N/A	NP_004951.1	P35637-1
	FUS	NM_001170634.1		c.1391-2delA		splice_acceptor intron	N/A	NP_001164105.1	P35637-2
	FUS	NM_001170937.1		c.1382-2delA		splice_acceptor intron	N/A	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.1394-2delA		splice_acceptor intron	N/A	ENSP00000254108.8	P35637-1
	FUS	ENST00000380244.8	TSL:1	c.1391-2delA		splice_acceptor intron	N/A	ENSP00000369594.3	P35637-2
	FUS	ENST00000566605.5	TSL:1	n.*567-2delA		splice_acceptor intron	N/A	ENSP00000455073.1	H3BNZ4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Amyotrophic lateral sclerosis type 6 (1)
1	-	-	Amyotrophic lateral sclerosis type 6;C3539195:Tremor, hereditary essential, 4 (1)
1	-	-	FUS-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AL_spliceai		1.0		Position offset: 3

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

Other links and lift over

dbSNP: rs1555509569; hg19: chr16-31202281;