1-36468158-C-T
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.Trp547*) 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
Consequence
NM_000760.4 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000276 AC: 42AN: 152210Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000256 AC: 64AN: 250056Hom.: 0 AF XY: 0.000244 AC XY: 33AN XY: 135066
GnomAD4 exome AF: 0.000480 AC: 701AN: 1460948Hom.: 1 Cov.: 32 AF XY: 0.000446 AC XY: 324AN XY: 726754
GnomAD4 genome AF: 0.000276 AC: 42AN: 152328Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18AN XY: 74492
ClinVar
Submissions by phenotype
not provided Pathogenic:3
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) -
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). -
PP4, PM2, PM3, PS3_supporting, PVS1 -
Autosomal recessive severe congenital neutropenia due to CSF3R deficiency Pathogenic:2
- -
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. -
CSF3R-Related Disorders Pathogenic:1
Variant summary: CSF3R c.1640G>A (p.Trp547X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00026 in 250056 control chromosomes. c.1640G>A has been reported in the literature in at least one compound heterozygous individuals affected with congenital neutropenia (e.g. Klimiankou_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 26324699). ClinVar contains an entry for this variant (Variation ID: 570920). Based on the evidence outlined above, the variant was classified as pathogenic. -
Inherited Immunodeficiency Diseases Pathogenic:1
- -
Hereditary neutrophilia;C4310764:Autosomal recessive severe congenital neutropenia due to CSF3R deficiency Pathogenic:1
- -
CSF3R-related disorder Pathogenic:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at