rs148279552

Variant names:

• chr2-136115145-G-A
• rs148279552
• NM_003467.3:c.783C>T

Variant summary

Our verdict is Benign. The variant received -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 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 criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.142
• Publications: 6 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: Labcorp Genetics (formerly Invitae), G2P
• WHIM syndrome

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 434875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.142 with no splicing effect.
• BS2: High AC in GnomAd4 at 371 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003467.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXCR4	NM_003467.3	MANE Select	c.783C>T	p.Ile261Ile	synonymous	Exon 2 of 2	NP_003458.1	P61073-1
	CXCR4	NM_001348056.2		c.996C>T	p.Ile332Ile	synonymous	Exon 3 of 3	NP_001334985.1	A0A0U3GXA9
	CXCR4	NM_001348059.2		c.882C>T	p.Ile294Ile	synonymous	Exon 3 of 3	NP_001334988.1	A0A0U3FJG0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXCR4	ENST00000241393.4	TSL:1 MANE Select	c.783C>T	p.Ile261Ile	synonymous	Exon 2 of 2	ENSP00000241393.3	P61073-1
	CXCR4	ENST00000466288.1	TSL:1	c.738C>T	p.Ile246Ile	synonymous	Exon 2 of 2	ENSP00000512430.1	A0A8Q3WLL1
	CXCR4	ENST00000409817.1	TSL:6	c.795C>T	p.Ile265Ile	synonymous	Exon 1 of 1	ENSP00000386884.1	P61073-2

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

GnomAD2 exomes AF: 0.00274 AC: 689 AN: 251460 AF XY: 0.00293

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 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

African (AFR) AF: 0.000627 AC: 21 AN: 33480

American (AMR) AF: 0.00145 AC: 65 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00283 AC: 74 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.00332 AC: 286 AN: 86254

European-Finnish (FIN) AF: 0.00215 AC: 115 AN: 53418

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00422 AC: 4697 AN: 1112012

Other (OTH) AF: 0.00245 AC: 148 AN: 60396

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

African (AFR) AF: 0.000842 AC: 35 AN: 41564

American (AMR) AF: 0.00268 AC: 41 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4824

European-Finnish (FIN) AF: 0.00217 AC: 23 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00356 AC: 242 AN: 68026

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00348 Hom.: 0

Bravo AF: 0.00251

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	1	CXCR4-related disorder (1)
-	-	1	Warts, hypogammaglobulinemia, infections, and myelokathexis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	7.5
DANN	Benign	0.72
PhyloP100		-0.14
Mutation Taster		=99/1	polymorphism

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