rs148279552

Positions:

• chr2-136115145-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_003467.3(CXCR4):​c.783C>T​(p.Ile261Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00358 in 1,614,192 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (13 hom.)
• Consequence: CXCR4 NM_003467.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.142

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 Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 2-136115145-G-A is Benign according to our data. Variant chr2-136115145-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 434875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-136115145-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.142 with no splicing effect.
• BS2: High AC in GnomAd4 at 371 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CXCR4	NM_003467.3	c.783C>T	p.Ile261Ile	synonymous_variant	2/2	ENST00000241393.4	NP_003458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CXCR4	ENST00000241393.4	c.783C>T	p.Ile261Ile	synonymous_variant	2/2	1	NM_003467.3	ENSP00000241393.3

Frequencies

GnomAD3 genomes AF: 0.00244 AC: 372 AN: 152186 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00356

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00274 AC: 689 AN: 251460 Hom.: 1 AF XY: 0.00293 AC XY: 398 AN XY: 135906

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00297

Gnomad FIN exome AF: 0.00217

Gnomad NFE exome AF: 0.00394

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00370 AC: 5415 AN: 1461888 Hom.: 13 Cov.: 31 AF XY: 0.00379 AC XY: 2756 AN XY: 727246

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.00283

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00332

Gnomad4 FIN exome AF: 0.00215

Gnomad4 NFE exome AF: 0.00422

Gnomad4 OTH exome AF: 0.00245

GnomAD4 genome AF: 0.00244 AC: 371 AN: 152304 Hom.: 1 Cov.: 32 AF XY: 0.00256 AC XY: 191 AN XY: 74470

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.00356

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00358 Hom.: 0

Bravo AF: 0.00251

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CXCR4: BP4, BP7, BS1 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 21, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 15, 2018	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

CXCR4-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 06, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Warts, hypogammaglobulinemia, infections, and myelokathexis Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	7.5
DANN	Benign	0.72

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: rs148279552; hg19: chr2-136872715; COSMIC: COSV54010958;