16-31180164-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004960.4(FUS):​c.-51C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000936 in 1,602,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

FUS
NM_004960.4 5_prime_UTR

Scores

2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.590

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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
  • 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: Likely_benign. The variant received -4 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.76).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FUSNM_004960.4 linkc.-51C>T 5_prime_UTR_variant Exon 1 of 15 ENST00000254108.12 NP_004951.1 P35637-1Q6IBQ5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FUSENST00000254108.12 linkc.-51C>T 5_prime_UTR_variant Exon 1 of 15 1 NM_004960.4 ENSP00000254108.8 P35637-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152230
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.000478
GnomAD2 exomes
AF:
0.0000132
AC:
3
AN:
227194
AF XY:
0.0000163
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000296
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000828
AC:
12
AN:
1449872
Hom.:
0
Cov.:
35
AF XY:
0.00000972
AC XY:
7
AN XY:
720118
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33332
American (AMR)
AF:
0.00
AC:
0
AN:
42734
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25856
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39184
South Asian (SAS)
AF:
0.0000118
AC:
1
AN:
84476
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52286
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5752
European-Non Finnish (NFE)
AF:
0.00000994
AC:
11
AN:
1106346
Other (OTH)
AF:
0.00
AC:
0
AN:
59906
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.496
Heterozygous variant carriers
0
1
2
4
5
6
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:
0.0000197
AC:
3
AN:
152348
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74498
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41588
American (AMR)
AF:
0.0000653
AC:
1
AN:
15310
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5166
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10628
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68034
Other (OTH)
AF:
0.000473
AC:
1
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.442
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
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Amyotrophic lateral sclerosis type 6 Uncertain:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.76
CADD
Benign
7.3
DANN
Benign
0.81
PhyloP100
-0.59
PromoterAI
-0.014
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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: rs571696003; hg19: chr16-31191485; COSMIC: COSV54217578; COSMIC: COSV54217578; API