GeneBe

16-31191408-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004960.4(FUS):​c.1551C>T​(p.His517His) variant causes a synonymous change. The variant allele was found at a frequency of 0.00000186 in 1,608,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FUS
NM_004960.4 synonymous

Scores

2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.79

Publications

65 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)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.36).

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.1551C>Tp.His517His
synonymous
Exon 15 of 15NP_004951.1P35637-1
FUS
NM_001170634.1
c.1548C>Tp.His516His
synonymous
Exon 15 of 15NP_001164105.1P35637-2
FUS
NM_001170937.1
c.1539C>Tp.His513His
synonymous
Exon 15 of 15NP_001164408.1Q13344

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
FUS
ENST00000254108.12
TSL:1 MANE Select
c.1551C>Tp.His517His
synonymous
Exon 15 of 15ENSP00000254108.8P35637-1
FUS
ENST00000380244.8
TSL:1
c.1548C>Tp.His516His
synonymous
Exon 15 of 15ENSP00000369594.3P35637-2
FUS
ENST00000566605.5
TSL:1
n.*724C>T
non_coding_transcript_exon
Exon 14 of 14ENSP00000455073.1H3BNZ4

Frequencies

GnomAD3 genomes
AF:
0.0000135
AC:
2
AN:
147608
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000252
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:
0.0000149
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461270
Hom.:
0
Cov.:
36
AF XY:
0.00
AC XY:
0
AN XY:
726940
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.0000299
AC:
1
AN:
33456
American (AMR)
AF:
0.00
AC:
0
AN:
44712
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26130
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39692
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86236
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53390
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5634
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111674
Other (OTH)
AF:
0.00
AC:
0
AN:
60346
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.325
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

Exome 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
GnomAD4 genome
AF:
0.0000135
AC:
2
AN:
147608
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
71618
show subpopulations
African (AFR)
AF:
0.0000252
AC:
1
AN:
39650
American (AMR)
AF:
0.00
AC:
0
AN:
14716
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3440
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5070
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4686
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
9552
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
308
European-Non Finnish (NFE)
AF:
0.0000149
AC:
1
AN:
67242
Other (OTH)
AF:
0.00
AC:
0
AN:
2034
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
Alfa
AF:
0.00
Hom.:
0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.36
CADD
Benign
8.7
DANN
Benign
0.88
PhyloP100
3.8
RBP_binding_hub_radar
1.1
RBP_regulation_power_radar
2.8

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.15
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs121909667; hg19: chr16-31202729; API