rs138901914
Positions:
Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2
The NM_004960.4(FUS):c.1566G>A(p.Arg522=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,613,152 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0010 ( 1 hom., cov: 31)
Exomes 𝑓: 0.0018 ( 7 hom. )
Consequence
FUS
NM_004960.4 synonymous
NM_004960.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.774
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -19 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.42).
BP6
?
Variant 16-31191423-G-A is Benign according to our data. Variant chr16-31191423-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 540280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-31191423-G-A is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=0.774 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.001 (152/151422) while in subpopulation SAS AF= 0.0021 (10/4764). AF 95% confidence interval is 0.00147. There are 1 homozygotes in gnomad4. There are 71 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAdExome4 at 7 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FUS | NM_004960.4 | c.1566G>A | p.Arg522= | synonymous_variant | 15/15 | ENST00000254108.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FUS | ENST00000254108.12 | c.1566G>A | p.Arg522= | synonymous_variant | 15/15 | 1 | NM_004960.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000991 AC: 150AN: 151304Hom.: 0 Cov.: 31
GnomAD3 genomes
?
AF:
AC:
150
AN:
151304
Hom.:
Cov.:
31
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00131 AC: 329AN: 251420Hom.: 2 AF XY: 0.00149 AC XY: 203AN XY: 135882
GnomAD3 exomes
AF:
AC:
329
AN:
251420
Hom.:
AF XY:
AC XY:
203
AN XY:
135882
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00181 AC: 2649AN: 1461730Hom.: 7 Cov.: 36 AF XY: 0.00192 AC XY: 1397AN XY: 727176
GnomAD4 exome
AF:
AC:
2649
AN:
1461730
Hom.:
Cov.:
36
AF XY:
AC XY:
1397
AN XY:
727176
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.00100 AC: 152AN: 151422Hom.: 1 Cov.: 31 AF XY: 0.000960 AC XY: 71AN XY: 73984
GnomAD4 genome
?
AF:
AC:
152
AN:
151422
Hom.:
Cov.:
31
AF XY:
AC XY:
71
AN XY:
73984
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:6
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 13, 2017 | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 18, 2021 | This variant is associated with the following publications: (PMID: 26176978, 22292843, 25585530, 19861302, 26725112, 20138404, 21261515, 29670510) - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | FUS: BP4, BP7 - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 09, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Amyotrophic lateral sclerosis type 6 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Tremor, hereditary essential, 4 Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
Amyotrophic lateral sclerosis type 6;C3539195:Tremor, hereditary essential, 4 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at