NM_003467.3:c.16-67T>A

Variant names:

• chr2-136115979-A-T
• rs2680880
• NM_003467.3:c.16-67T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003467.3(CXCR4):​c.16-67T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.499 in 1,611,214 control chromosomes in the GnomAD database, including 230,646 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (12530 hom., cov: 31)
  • Exomes 𝑓: 0.52 (218116 hom.)
• Consequence: CXCR4 NM_003467.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.403
• Publications: 17 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-136115979-A-T is Benign according to our data. Variant chr2-136115979-A-T is described in ClinVar as Benign. ClinVar VariationId is 1249487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.532 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CXCR4	NM_003467.3	c.16-67T>A		intron_variant	Intron 1 of 1	ENST00000241393.4	NP_003458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CXCR4	ENST00000241393.4	c.16-67T>A		intron_variant	Intron 1 of 1	1	NM_003467.3	ENSP00000241393.3

Frequencies

GnomAD3 genomes AF: 0.346 AC: 52474 AN: 151866 Hom.: 12532 Cov.: 31

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.606

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.00347

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.459

Gnomad MID AF: 0.137

Gnomad NFE AF: 0.537

Gnomad OTH AF: 0.277

GnomAD2 exomes AF: 0.358 AC: 86321 AN: 241100 AF XY: 0.368

Gnomad AFR exome AF: 0.0954

Gnomad AMR exome AF: 0.195

Gnomad ASJ exome AF: 0.188

Gnomad EAS exome AF: 0.00127

Gnomad FIN exome AF: 0.457

Gnomad NFE exome AF: 0.522

Gnomad OTH exome AF: 0.353

GnomAD4 exome AF: 0.515 AC: 752143 AN: 1459230 Hom.: 218116 Cov.: 41 AF XY: 0.506 AC XY: 367509 AN XY: 725830

African (AFR) AF: 0.0808 AC: 2703 AN: 33452

American (AMR) AF: 0.202 AC: 9018 AN: 44540

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 4918 AN: 26116

East Asian (EAS) AF: 0.00113 AC: 45 AN: 39696

South Asian (SAS) AF: 0.300 AC: 25793 AN: 85930

European-Finnish (FIN) AF: 0.460 AC: 24188 AN: 52600

Middle Eastern (MID) AF: 0.127 AC: 730 AN: 5764

European-Non Finnish (NFE) AF: 0.593 AC: 658472 AN: 1110818

Other (OTH) AF: 0.436 AC: 26276 AN: 60314

GnomAD4 genome AF: 0.345 AC: 52471 AN: 151984 Hom.: 12530 Cov.: 31 AF XY: 0.334 AC XY: 24812 AN XY: 74276

African (AFR) AF: 0.105 AC: 4358 AN: 41510

American (AMR) AF: 0.239 AC: 3643 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 696 AN: 3470

East Asian (EAS) AF: 0.00347 AC: 18 AN: 5182

South Asian (SAS) AF: 0.265 AC: 1274 AN: 4808

European-Finnish (FIN) AF: 0.459 AC: 4830 AN: 10512

Middle Eastern (MID) AF: 0.134 AC: 39 AN: 292

European-Non Finnish (NFE) AF: 0.537 AC: 36486 AN: 67932

Other (OTH) AF: 0.273 AC: 577 AN: 2110

Alfa AF: 0.387 Hom.: 2506

Bravo AF: 0.316

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 11, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 36% of patients studied by a panel of primary immunodeficiencies. Number of patients: 32. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.10
DANN	Benign	0.31
PhyloP100		-0.40
PromoterAI		-0.015	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2680880; hg19: chr2-136873549; COSMIC: COSV54013092;