rs730880320

Variant names:

• chr2-136114910-CAG-C
• rs730880320
• NM_003467.3:c.1016_1017delCT

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_003467.3(CXCR4):​c.1016_1017delCT​(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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CXCR4 NM_003467.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.60
• Publications: 13 publications found

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]

CXCR4 Gene-Disease associations (from GenCC):

• WHIM syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• WHIM syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• WHIM syndrome

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 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. There are 13 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 Pathogenic. ClinVar VariationId is 14021.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003467.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXCR4	NM_003467.3	MANE Select	c.1016_1017delCT	p.Ser339CysfsTer4	frameshift	Exon 2 of 2	NP_003458.1
	CXCR4	NM_001348056.2		c.1229_1230delCT	p.Ser410CysfsTer4	frameshift	Exon 3 of 3	NP_001334985.1
	CXCR4	NM_001348059.2		c.1115_1116delCT	p.Ser372CysfsTer4	frameshift	Exon 3 of 3	NP_001334988.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXCR4	ENST00000241393.4	TSL:1 MANE Select	c.1016_1017delCT	p.Ser339CysfsTer4	frameshift	Exon 2 of 2	ENSP00000241393.3
	CXCR4	ENST00000466288.1	TSL:1	c.971_972delCT	p.Ser324CysfsTer4	frameshift	Exon 2 of 2	ENSP00000512430.1
	CXCR4	ENST00000409817.1	TSL:6	c.1028_1029delCT	p.Ser343CysfsTer4	frameshift	Exon 1 of 1	ENSP00000386884.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

WHIM syndrome 1 Pathogenic:1

May 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Warts, hypogammaglobulinemia, infections, and myelokathexis Pathogenic:1

May 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ser339Cysfs*4) in the CXCR4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 14 amino acid(s) of the CXCR4 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with clinical features of WHIM syndrome (PMID: 12692554, 16899028; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14021). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects CXCR4 function (PMID: 16899028). For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.6
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs730880320; hg19: chr2-136872480;