chr2-136114901-C-A

Variant names:

• chr2-136114901-C-A
• rs104893625
• NM_003467.3:c.1027G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_003467.3(CXCR4):​c.1027G>T​(p.Glu343*) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CXCR4 NM_003467.3 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.57

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 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 0.0302 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-136114901-C-A is Pathogenic according to our data. Variant chr2-136114901-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14022.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CXCR4	NM_003467.3	c.1027G>T	p.Glu343*	stop_gained	Exon 2 of 2	ENST00000241393.4	NP_003458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CXCR4	ENST00000241393.4	c.1027G>T	p.Glu343*	stop_gained	Exon 2 of 2	1	NM_003467.3	ENSP00000241393.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

WHIM syndrome 1 Pathogenic:2

May 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 14, 2025

Research Department, X4 Pharmaceuticals (Austria) GmbH

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation;in vitro

The p.E343K missense variant has been observed in individuals with WHIM syndrome (PMID: 22596258), and has also been observed to segregate with disease in related individuals. . Experimental studies have shown that this missense change affects CXCR4 function (PMID: 22596258, 23734232, 33485325, 36089616). This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.97	D
Vest4		0.79
GERP RS		6.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs104893625; hg19: chr2-136872471;