rs150529460
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_004960.4(FUS):c.1464C>T(p.Gly488=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000484 in 1,611,786 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00081 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00045 ( 3 hom. )
Consequence
FUS
NM_004960.4 synonymous
NM_004960.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -4.48
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.75).
BP6
?
Variant 16-31191033-C-T is Benign according to our data. Variant chr16-31191033-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 259593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-31191033-C-T is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=-4.48 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000814 (123/151180) while in subpopulation AMR AF= 0.00428 (65/15174). AF 95% confidence interval is 0.00345. There are 1 homozygotes in gnomad4. There are 57 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAdExome4 at 3 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FUS | NM_004960.4 | c.1464C>T | p.Gly488= | synonymous_variant | 14/15 | ENST00000254108.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FUS | ENST00000254108.12 | c.1464C>T | p.Gly488= | synonymous_variant | 14/15 | 1 | NM_004960.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000814 AC: 123AN: 151054Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.00105 AC: 262AN: 249364Hom.: 3 AF XY: 0.000849 AC XY: 115AN XY: 135430
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GnomAD4 exome AF: 0.000450 AC: 657AN: 1460606Hom.: 3 Cov.: 33 AF XY: 0.000434 AC XY: 315AN XY: 726626
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GnomAD4 genome ? AF: 0.000814 AC: 123AN: 151180Hom.: 1 Cov.: 32 AF XY: 0.000772 AC XY: 57AN XY: 73862
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:3
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 24, 2023 | 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 | Jun 14, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. - |
Amyotrophic lateral sclerosis type 6;C3539195:Tremor, hereditary essential, 4 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Dec 20, 2023 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at