chr2-136114915-G-C

Position:

• chr2-136114915-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_003467.3(CXCR4):​c.1013C>G​(p.Ser338*) variant causes a stop gained change involving the alteration of a 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CXCR4 NM_003467.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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 0.0434 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-136114915-G-C is Pathogenic according to our data. Variant chr2-136114915-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 14023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CXCR4	NM_003467.3	c.1013C>G	p.Ser338*	stop_gained	2/2	ENST00000241393.4	NP_003458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CXCR4	ENST00000241393.4	c.1013C>G	p.Ser338*	stop_gained	2/2	1	NM_003467.3	ENSP00000241393.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

WHIM syndrome 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	CXCR4 NM_003467 exon 2 p.Ser338* (c.1013C>G): This variant has been reported in the literature in at least 2 individuals with WHIM syndrome (warts, hypogammaglobulinemia, infection, and myelokathexis), segregating with disease in 1 affected family member (Balabanian 2005 PMID:15536153, Alapi 2007 PMID:17087743, Lagane 2008 PMID:18436740). One of these individuals was found to have this variant de novo. This variant is not present in large control databases. Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant creates a premature stop at this codon which results in an absent or abnormal protein. Loss of function variants have been reported in association with disease for this gene. Additional functional studies have shown a deleterious effect of this variant (Balabanian 2005 PMID:15536153, Lagane 2008 PMID:18436740). In summary, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 01, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2008	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 23, 2019	The CXCR4 c.1013C>G; p.Ser338Ter variant (rs104893626) is reported in the literature in several individuals affected with WHIM syndrome (Alapi 2007, Balabanian 2005, Tassone 2009). In one instance, the variant was observed in an affected proband but was absent from both parents, suggesting a de novo origin (Alapi 2007). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the CXCR4 gene. While this may not lead to nonsense-mediated decay, it is expected to truncate 15 amino acids from the C-terminal domain, including several residues functionally critical for receptor internalization (Orsini 1999). Indeed, functional characterization of patient cells or cultured cells expressing the p.Ser338Ter variant suggests the variant protein exhibits defective internalization, aberrant interactions with binding partners, and increased signaling activity (Balabanian 2005, Lagane 2008, Tassone 2009). Based on available information, the p.Ser338Ter variant is considered to be pathogenic. References: Alapi K et al. Recurrent CXCR4 sequence variation in a girl with WHIM syndrome. Eur J Haematol. 2007 Jan;78(1):86-8. Balabanian K et al. WHIM syndromes with different genetic anomalies are accounted for by impaired CXCR4 desensitization to CXCL12. Blood. 2005 Mar 15;105(6):2449-57. Lagane B et al. CXCR4 dimerization and beta-arrestin-mediated signaling account for the enhanced chemotaxis to CXCL12 in WHIM syndrome. Blood. 2008 Jul 1;112(1):34-44. Orsini MJ et al. Trafficking of the HIV coreceptor CXCR4. Role of arrestins and identification of residues in the c-terminal tail that mediate receptor internalization. J Biol Chem. 1999 Oct 22;274(43):31076-86. Tassone L et al. Clinical and genetic diagnosis of warts, hypogammaglobulinemia, infections, and myelokathexis syndrome in 10 patients. J Allergy Clin Immunol. 2009 May;123(5):1170-3, 1173.e1-3. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 09, 2019	Published functional studies demonstrate a damaging effect with delayed or failed receptor internalization (Balabanian et al., 2005); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 15 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26659815, 19321197, 15536153, 23009155, 19878273, 25819228, 25371371, 18436740, 26997321, 17087743) -

Warts, hypogammaglobulinemia, infections, and myelokathexis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Nov 02, 2017

CXCR4 NM_003467.2 exon 2 p.Ser338* (c.1013C>G): This variant has been reported in the literature in at least 2 individuals with WHIM syndrome (warts, hypogammaglobulinemia, infection, and myelokathexis), segregating with disease in 1 affected family member (Balabanian 2005 PMID:15536153, Alapi 2007 PMID:17087743, Lagane 2008 PMID:18436740). One of these individuals was found to have this variant de novo. This variant is not present in large control databases. Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant creates a premature stop at this codon which results in an absent or abnormal protein. Loss of function variants have been reported in association with disease for this gene. Additional functional studies have shown a deleterious effect of this variant (Balabanian 2005 PMID:15536153, Lagane 2008 PMID:18436740). In summary, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
Vest4		0.81
GERP RS		6.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs104893626; hg19: chr2-136872485; COSMIC: COSV54009912;