rs138156467
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 18P and 1B. PVS1PM2PP5_Very_StrongBS1_Supporting
The NM_000760.4(CSF3R):c.1640G>A(p.Trp547Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000461 in 1,613,276 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00028 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00048 ( 1 hom. )
Consequence
CSF3R
NM_000760.4 stop_gained
NM_000760.4 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.77
Genes affected
CSF3R (HGNC:2439): (colony stimulating factor 3 receptor) The protein encoded by this gene is the receptor for colony stimulating factor 3, a cytokine that controls the production, differentiation, and function of granulocytes. The encoded protein, which is a member of the family of cytokine receptors, may also function in some cell surface adhesion or recognition processes. Alternatively spliced transcript variants have been described. Mutations in this gene are a cause of Kostmann syndrome, also known as severe congenital neutropenia. [provided by RefSeq, Aug 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 17 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 1-36468158-C-T is Pathogenic according to our data. Variant chr1-36468158-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 570920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00048 (701/1460948) while in subpopulation NFE AF= 0.000608 (676/1111494). AF 95% confidence interval is 0.00057. There are 1 homozygotes in gnomad4_exome. There are 324 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CSF3R | NM_000760.4 | c.1640G>A | p.Trp547Ter | stop_gained | 13/17 | ENST00000373106.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CSF3R | ENST00000373106.6 | c.1640G>A | p.Trp547Ter | stop_gained | 13/17 | 1 | NM_000760.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000276 AC: 42AN: 152210Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000256 AC: 64AN: 250056Hom.: 0 AF XY: 0.000244 AC XY: 33AN XY: 135066
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GnomAD4 exome AF: 0.000480 AC: 701AN: 1460948Hom.: 1 Cov.: 32 AF XY: 0.000446 AC XY: 324AN XY: 726754
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive severe congenital neutropenia due to CSF3R deficiency Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | This sequence change creates a premature translational stop signal (p.Trp547*) in the CSF3R gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CSF3R are known to be pathogenic (PMID: 24753537, 26324699). This variant is present in population databases (rs138156467, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with autosomal recessive congenital neutropenia (PMID: 26324699). ClinVar contains an entry for this variant (Variation ID: 570920). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 05, 2016 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 12, 2021 | DNA sequence analysis of the CSF3R gene demonstrated a sequence change, c.1640G>A, which results in the creation of a premature stop codon at amino acid position 547, p.Trp547*. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated CSF3R protein with potentially abnormal function. This sequence change was identified in a compound heterozygous state with a second splice site pathogenic variant in a patient with congenital neutropenia (CN) (PMID: 26324699). Loss-of-function variants in CSF3R have been reported in patients with neutropenia (PMID: 24753537, 26324699). - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 15, 2023 | Identified in the heterozygous state in the published literature in patients with myelodysplasic syndrome, but additional clinical information was not provided (Trottier et al., 2019; Trottier et al., 2020; Feurstein et al., 2021); Published functional studies demonstrate loss of function of the gene product (Trottier et al., 2020); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32499645, 32888494, 33108454, 35178734, 31345219, 34778134, 33510405, 32966608, 26324699) - |
CSF3R-related condition Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 29, 2023 | The CSF3R c.1640G>A variant is predicted to result in premature protein termination (p.Trp547*). This variant has been reported in the compound heterozygous state in a patient with congenital neutropenia (Klimiankou et al. 2015. PubMed ID: 26324699) and also in a patient with history of bladder cancer who developed therapy-related myelodysplastic syndrome (Trottier et al. 2019., https://doi.org/10.1182/blood-2019-129492). This variant is reported in 0.051% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in CSF3R are expected to be pathogenic. This variant is interpreted as likely pathogenic. - |
Inherited Immunodeficiency Diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2019 | - - |
Hereditary neutrophilia;C4310764:Autosomal recessive severe congenital neutropenia due to CSF3R deficiency Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 21, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;A;A;A;A;A
Vest4
ClinPred
D
GERP RS
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