rs730880320
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate
The NM_003467.3(CXCR4):c.1016_1017del(p.Ser339CysfsTer4) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
CXCR4
NM_003467.3 frameshift
NM_003467.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.60
Genes affected
CXCR4 (HGNC:2561): (C-X-C motif chemokine receptor 4) This gene encodes a CXC chemokine receptor specific for stromal cell-derived factor-1. The protein has 7 transmembrane regions and is located on the cell surface. It acts with the CD4 protein to support HIV entry into cells and is also highly expressed in breast cancer cells. Mutations in this gene have been associated with WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0406 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 2-136114910-CAG-C is Pathogenic according to our data. Variant chr2-136114910-CAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14021.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CXCR4 | NM_003467.3 | c.1016_1017del | p.Ser339CysfsTer4 | frameshift_variant | 2/2 | ENST00000241393.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CXCR4 | ENST00000241393.4 | c.1016_1017del | p.Ser339CysfsTer4 | frameshift_variant | 2/2 | 1 | NM_003467.3 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
WHIM syndrome 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2003 | - - |
Warts, hypogammaglobulinemia, infections, and myelokathexis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 21, 2019 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has been reported to affect CXCR4 protein function (PMID: 16899028). This variant has been observed in several individuals with clinical features of WHIM syndrome (PMID: 12692554, 16899028, Invitae). ClinVar contains an entry for this variant (Variation ID: 14021). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the CXCR4 gene (p.Ser339Cysfs*4). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 14 amino acids of the CXCR4 protein. - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
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Calibrated prediction
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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