chr16-31190960-TA-T

Position:

• chr16-31190960-TA-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 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 (★★).

• 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

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 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.
• 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 [Likely_pathogenic]. Clinvar id is 447355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-31190960-TA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FUS	NM_004960.4	c.1394-2delA		splice_acceptor_variant, intron_variant		ENST00000254108.12	NP_004951.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FUS	ENST00000254108.12	c.1394-2delA		splice_acceptor_variant, intron_variant		1	NM_004960.4	ENSP00000254108.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Feb 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 27, 2016	- -

FUS-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 31, 2024

The FUS c.1394-2delA variant is predicted to result in a deletion affecting a canonical splice site. This variant has been reported in individuals with amyotrophic lateral sclerosis (ALS, Table 2, Cady et al. 2015. PubMed ID: 25382069) and frontotemporal dementia (FTD, Table S1, Wagner et al. 2021. PubMed ID: 34561610). It has also been reported to have arisen de novo in a Chinese individual with ALS (Figure 1, Yang et al. 2023. PubMed ID: 36511129). 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). This variant has not been reported the gnomAD database, indicating this variant is rare. Of note, additional splice-altering variants at the same acceptor site have been reported in individuals with ALS (c.1394-2A>G, DeJesus-Hernandez et al. 2010. PubMed ID: 20232451; c.1394-1G>T, Tunca et al. 2020. PubMed ID: 32579787; c.1394-1G>C, Chen et al. 2022. PubMed ID: 34544842). Loss of function variants in FUS are expected to be pathogenic. Taken together, the c.1394-2delA variant is interpreted as pathogenic. -

Amyotrophic lateral sclerosis type 6 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Jun 07, 2019

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 20, 2021

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 447355). Disruption of this splice site has been observed in individuals with early-onset amyotrophic lateral sclerosis (PMID: 20232451, 25382069). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a splice site in intron 13 of the FUS gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FUS are known to be pathogenic (PMID: 20660363, 23217123). -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555509569; hg19: chr16-31202281;