2-136114925-C-T

Position:

chr2-136114925-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_003467.3(CXCR4):c.1003G>A(p.Gly335Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00013 in 1,612,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

CXCR4
NM_003467.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 7.57

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1984821).

BS2

High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CXCR4	NM_003467.3 linkuse as main transcript	c.1003G>A	p.Gly335Ser	missense_variant	2/2	ENST00000241393.4	NP_003458.1	P61073-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CXCR4	ENST00000241393.4 linkuse as main transcript	c.1003G>A	p.Gly335Ser	missense_variant	2/2	1	NM_003467.3	ENSP00000241393.3		P61073-1

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000605

AC:

AN:

247912

Hom.:

AF XY:

0.0000597

AC XY:

AN XY:

133906

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000134

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000136

AC:

198

AN:

1459970

Hom.:

Cov.:

AF XY:

0.000131

AC XY:

AN XY:

726046

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000174

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000987

Hom.:

Bravo

AF:

0.0000907

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 2022	Identified in an individual with familial chronic lymphocytic leukemia (Crowther-Swanepoel et al., 2009); however, familial segregation analysis was not performed and additional clinical details were not provided; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27268124, 19812382, 33735664) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 19, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 26, 2018	- -

not specified

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 19, 2022

DNA sequence analysis of the CXCR4 gene demonstrated a sequence change, c.1003G>A, in exon 2 that results in an amino acid change, p.Gly335Ser. This sequence change does not appear to have been previously described in individuals with CXCR4-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.013% in the European subpopulation (dbSNP rs147214773). The p.Gly335Ser change affects a moderately conserved amino acid residue located in a domain of the CXCR4 protein that is known to be functional. The p.Gly335Ser substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been reported in one individual with familial chronic lymphocytic leukemia (PMID:19812382). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Gly335Ser change remains unknown at this time. -

Warts, hypogammaglobulinemia, infections, and myelokathexis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

.;T

Eigen

Benign

0.015

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.20

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.5

.;L

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.51

N;N

REVEL

Benign

0.12

Sift

Uncertain

0.0020

D;D

Sift4G

Benign

0.41

T;T

Polyphen

0.65

P;B

Vest4

0.35

MVP

0.68

MPC

0.90

ClinPred

0.70

GERP RS

6.0

Varity_R

0.10

gMVP

0.50

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