Genetic Variant NM_004960.4:c.1553G>A (chr16-31191410-G-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP5_Moderate

The NM_004960.4(FUS):c.1553G>A(p.Arg518Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R518G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Consequence

FUS
NM_004960.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 8.17

Publications

44 publications found

Variant links:

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)

FUS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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, 13 uncertain in NM_004960.4

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-31191410-G-A is Pathogenic according to our data. Variant chr16-31191410-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 16223.Status of the report is criteria_provided_single_submitter, 1 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FUS	NM_004960.4	MANE Select	c.1553G>A	p.Arg518Lys	missense	Exon 15 of 15	NP_004951.1	P35637-1
FUS	NM_001170634.1		c.1550G>A	p.Arg517Lys	missense	Exon 15 of 15	NP_001164105.1	P35637-2
FUS	NM_001170937.1		c.1541G>A	p.Arg514Lys	missense	Exon 15 of 15	NP_001164408.1	Q13344

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FUS	ENST00000254108.12	TSL:1 MANE Select	c.1553G>A	p.Arg518Lys	missense	Exon 15 of 15	ENSP00000254108.8	P35637-1
FUS	ENST00000380244.8	TSL:1	c.1550G>A	p.Arg517Lys	missense	Exon 15 of 15	ENSP00000369594.3	P35637-2
FUS	ENST00000566605.5	TSL:1	n.*726G>A		non_coding_transcript_exon	Exon 14 of 14	ENSP00000455073.1	H3BNZ4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Amyotrophic lateral sclerosis type 6 (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

0.85

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.62

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.75

M_CAP

Uncertain

0.28

MetaRNN

Uncertain

0.72

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.4

PhyloP100

8.2

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.9

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0060

Polyphen

0.96

Vest4

0.46

MutPred

0.80

Gain of methylation at R518 (P = 0.0114)

MVP

0.97

MPC

1.4

ClinPred

0.97

GERP RS

4.8

Varity_R

0.93

gMVP

0.94

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over