Genetic Variant CXCR4:c.16-67T>A (chr2-136115979-A-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001008540.2(CXCR4):c.-40T>A variant causes a 5 prime UTR 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_001008540.2 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.403

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 -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 id 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 link	c.16-67T>A		intron_variant	Intron 1 of 1	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.16-67T>A		intron_variant	Intron 1 of 1	1	NM_003467.3	ENSP00000241393.3		P61073-1

Frequencies

GnomAD3 genomes

AF:

0.346

AC:

52474

AN:

151866

Hom.:

12532

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.358

AC:

86321

AN:

241100

Hom.:

20516

AF XY:

0.368

AC XY:

48602

AN XY:

132008

show subpopulations

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 SAS exome

AF:

0.292

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.:

AF XY:

0.506

AC XY:

367509

AN XY:

725830

show subpopulations

Gnomad4 AFR exome

AF:

0.0808

Gnomad4 AMR exome

AF:

0.202

Gnomad4 ASJ exome

AF:

0.188

Gnomad4 EAS exome

AF:

0.00113

Gnomad4 SAS exome

AF:

0.300

Gnomad4 FIN exome

AF:

0.460

Gnomad4 NFE exome

AF:

0.593

Gnomad4 OTH exome

AF:

0.436

GnomAD4 genome

AF:

0.345

AC:

52471

AN:

151984

Hom.:

12530

Cov.:

AF XY:

0.334

AC XY:

24812

AN XY:

74276

show subpopulations

Gnomad4 AFR

AF:

0.105

Gnomad4 AMR

AF:

0.239

Gnomad4 ASJ

AF:

0.201

Gnomad4 EAS

AF:

0.00347

Gnomad4 SAS

AF:

0.265

Gnomad4 FIN

AF:

0.459

Gnomad4 NFE

AF:

0.537

Gnomad4 OTH

AF:

0.273

Alfa

AF:

0.387

Hom.:

2506

Bravo

AF:

0.316

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 11, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

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