dbSNP rs148279552: CXCR4:p.Ile261Ile (chr2-136115145-G-A) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

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 Benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 13 hom. )

Consequence

CXCR4
NM_003467.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.142

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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 [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 rank	MANE	Protein	UniProt
CXCR4	NM_003467.3 link	c.783C>T	p.Ile261Ile	synonymous_variant	Exon 2 of 2	ENST00000241393.4	NP_003458.1	P61073-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CXCR4	ENST00000241393.4 link	c.783C>T	p.Ile261Ile	synonymous_variant	Exon 2 of 2	1	NM_003467.3	ENSP00000241393.3		P61073-1

Frequencies

GnomAD3 genomes

AF:

0.00244

AC:

372

AN:

152186

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00293

AC XY:

398

AN XY:

135906

show subpopulations

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.:

Cov.:

AF XY:

0.00379

AC XY:

2756

AN XY:

727246

show subpopulations

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.:

Cov.:

AF XY:

0.00256

AC XY:

191

AN XY:

74470

show subpopulations

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.:

Bravo

AF:

0.00251

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CXCR4: BP4, BP7, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 07, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Feb 15, 2018

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

CXCR4-related disorder

Benign:1

Sep 06, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over