rs2228014

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003467.3(CXCR4):c.414C>T(p.Ile138Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0391 in 1,614,162 control chromosomes in the GnomAD database, including 1,655 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.037 ( 171 hom., cov: 32)

Exomes 𝑓: 0.039 ( 1484 hom. )

Consequence

CXCR4
NM_003467.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.486

Publications

66 publications found

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 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

CXCR4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 2-136115514-G-A is Benign according to our data. Variant chr2-136115514-G-A is described in ClinVar as Benign. ClinVar VariationId is 259052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.486 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CXCR4	NM_003467.3 link	c.414C>T	p.Ile138Ile	synonymous_variant	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 link	c.414C>T	p.Ile138Ile	synonymous_variant	Exon 2 of 2	1	NM_003467.3	ENSP00000241393.3

Frequencies

GnomAD3 genomes

AF:

0.0368

AC:

5594

AN:

152154

Hom.:

169

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0179

Gnomad AMI

AF:

0.0771

Gnomad AMR

AF:

0.0329

Gnomad ASJ

AF:

0.0746

Gnomad EAS

AF:

0.122

Gnomad SAS

AF:

0.0814

Gnomad FIN

AF:

0.00960

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0407

Gnomad OTH

AF:

0.0484

GnomAD2 exomes

AF:

0.0457

AC:

11496

AN:

251468

AF XY:

0.0483

show subpopulations

Gnomad AFR exome

AF:

0.0184

Gnomad AMR exome

AF:

0.0201

Gnomad ASJ exome

AF:

0.0720

Gnomad EAS exome

AF:

0.126

Gnomad FIN exome

AF:

0.0110

Gnomad NFE exome

AF:

0.0394

Gnomad OTH exome

AF:

0.0427

GnomAD4 exome

AF:

0.0394

AC:

57578

AN:

1461890

Hom.:

1484

Cov.:

AF XY:

0.0412

AC XY:

29935

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.0168

AC:

563

AN:

33480

American (AMR)

AF:

0.0214

AC:

959

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0732

AC:

1913

AN:

26136

East Asian (EAS)

AF:

0.0977

AC:

3877

AN:

39700

South Asian (SAS)

AF:

0.0791

AC:

6819

AN:

86258

European-Finnish (FIN)

AF:

0.0128

AC:

685

AN:

53418

Middle Eastern (MID)

AF:

0.0685

AC:

395

AN:

5768

European-Non Finnish (NFE)

AF:

0.0356

AC:

39587

AN:

1112010

Other (OTH)

AF:

0.0460

AC:

2780

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

3782

7565

11347

15130

18912

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1478

2956

4434

5912

7390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0368

AC:

5597

AN:

152272

Hom.:

171

Cov.:

AF XY:

0.0377

AC XY:

2804

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0179

AC:

744

AN:

41556

American (AMR)

AF:

0.0329

AC:

503

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0746

AC:

259

AN:

3470

East Asian (EAS)

AF:

0.123

AC:

638

AN:

5188

South Asian (SAS)

AF:

0.0813

AC:

392

AN:

4824

European-Finnish (FIN)

AF:

0.00960

AC:

102

AN:

10622

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0407

AC:

2768

AN:

68004

Other (OTH)

AF:

0.0483

AC:

102

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

263

526

790

1053

1316

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

222

296

370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0407

Hom.:

534

Bravo

AF:

0.0363

Asia WGS

AF:

0.0990

AC:

343

AN:

3478

EpiCase

AF:

0.0451

EpiControl

AF:

0.0468

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Sep 30, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 06, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 19473177, 31177127)

Warts, hypogammaglobulinemia, infections, and myelokathexis

Benign:1

Feb 03, 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

-0.74

CADD

Benign

2.3

(source)

DANN

Benign

0.83

PhyloP100

-0.49

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over