rs917027829
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001288705.3(CSF1R):c.1441C>T(p.Gln481Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
CSF1R
NM_001288705.3 stop_gained
NM_001288705.3 stop_gained
Scores
1
1
5
Clinical Significance
Conservation
PhyloP100: -0.180
Genes affected
CSF1R (HGNC:2433): (colony stimulating factor 1 receptor) The protein encoded by this gene is the receptor for colony stimulating factor 1, a cytokine which controls the production, differentiation, and function of macrophages. This receptor mediates most if not all of the biological effects of this cytokine. Ligand binding activates the receptor kinase through a process of oligomerization and transphosphorylation. The encoded protein is a tyrosine kinase transmembrane receptor and member of the CSF1/PDGF receptor family of tyrosine-protein kinases. Mutations in this gene have been associated with a predisposition to myeloid malignancy. The first intron of this gene contains a transcriptionally inactive ribosomal protein L7 processed pseudogene oriented in the opposite direction. Alternative splicing results in multiple transcript variants. Expression of a splice variant from an LTR promoter has been found in Hodgkin lymphoma (HL), HL cell lines and anaplastic large cell lymphoma. [provided by RefSeq, Mar 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 5-150069942-G-A is Pathogenic according to our data. Variant chr5-150069942-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 520697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CSF1R | NM_001288705.3 | c.1441C>T | p.Gln481Ter | stop_gained | 9/21 | ENST00000675795.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CSF1R | ENST00000675795.1 | c.1441C>T | p.Gln481Ter | stop_gained | 9/21 | NM_001288705.3 | P1 | ||
CSF1R | ENST00000286301.7 | c.1441C>T | p.Gln481Ter | stop_gained | 10/22 | 1 | P1 | ||
CSF1R | ENST00000504875.5 | c.1441C>T | p.Gln481Ter | stop_gained, NMD_transcript_variant | 9/20 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 18, 2023 | This variant is demonstrated to induce nonsense-mediated decay and result in loss of function (Guo et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30982609) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 22, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 520697). This premature translational stop signal has been observed in individuals with autosomal dominant CSF1R-related conditions (Invitae). This variant has been reported in individual(s) with autosomal recessive brain abnormalities, neurodegeneration, and dysosteosclerosis (PMID: 30982609); however, the role of the variant in this condition is currently unclear. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln481*) in the CSF1R gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CSF1R are known to be pathogenic (PMID: 24336230, 24120500, 24145216). - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 29, 2015 | - - |
Hereditary diffuse leukoencephalopathy with spheroids Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Mar 05, 2022 | The c.1441C>T;p.(Gln481*) variant creates a premature translational stop signal in the CSF1R gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 520697) - PS4. This variant is not present in population databases (rs917027829- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Brain abnormalities, neurodegeneration, and dysosteosclerosis Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 21, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
A
Vest4
GERP RS
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