GeneBe

16-31191069-TG-TGGGG

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PM4_Supporting

The NM_004960.4(FUS):​c.1502_1504dupGGG​(p.Gly501dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.00000662 in 151,124 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D502D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

FUS
NM_004960.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.63

Publications

0 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)

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_004960.4
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_004960.4. Strenght limited to Supporting due to length of the change: 1aa.

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.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
FUS
NM_004960.4
MANE Select
c.1502_1504dupGGGp.Gly501dup
disruptive_inframe_insertion
Exon 14 of 15NP_004951.1P35637-1
FUS
NM_001170634.1
c.1499_1501dupGGGp.Gly500dup
disruptive_inframe_insertion
Exon 14 of 15NP_001164105.1P35637-2
FUS
NM_001170937.1
c.1490_1492dupGGGp.Gly497dup
disruptive_inframe_insertion
Exon 14 of 15NP_001164408.1Q13344

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
FUS
ENST00000254108.12
TSL:1 MANE Select
c.1502_1504dupGGGp.Gly501dup
disruptive_inframe_insertion
Exon 14 of 15ENSP00000254108.8P35637-1
FUS
ENST00000380244.8
TSL:1
c.1499_1501dupGGGp.Gly500dup
disruptive_inframe_insertion
Exon 14 of 15ENSP00000369594.3P35637-2
FUS
ENST00000566605.5
TSL:1
n.*675_*677dupGGG
non_coding_transcript_exon
Exon 13 of 14ENSP00000455073.1H3BNZ4

Frequencies

GnomAD3 genomes
AF:
0.00000662
AC:
1
AN:
151124
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
33
GnomAD4 genome
AF:
0.00000662
AC:
1
AN:
151124
Hom.:
0
Cov.:
32
AF XY:
0.0000136
AC XY:
1
AN XY:
73756
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
40942
American (AMR)
AF:
0.00
AC:
0
AN:
15152
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3466
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5162
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4774
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10484
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
314
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
67846
Other (OTH)
AF:
0.00
AC:
0
AN:
2074
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
PhyloP100
4.6
Mutation Taster
=66/34
polymorphism

Splicing

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

Publications

Other links and lift over

dbSNP: rs1161032867; hg19: chr16-31202390; API