Variant 2-136114886-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_003467.3(CXCR4):c.1042A>G(p.Ser348Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,234 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CXCR4
NM_003467.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.67

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 Uncertain_significance. Variant got 4 ACMG points.

PM1

In a modified_residue Phosphoserine (size 0) in uniprot entity CXCR4_HUMAN

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CXCR4	NM_003467.3 linkuse as main transcript	c.1042A>G	p.Ser348Gly	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.1042A>G	p.Ser348Gly	missense_variant	2/2	1	NM_003467.3	ENSP00000241393.3		P61073-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457234

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724572

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Warts, hypogammaglobulinemia, infections, and myelokathexis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 04, 2023

This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1362599). This variant has not been reported in the literature in individuals affected with CXCR4-related conditions. This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 348 of the CXCR4 protein (p.Ser348Gly). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.29

.;T

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.78

T;T

M_CAP

Benign

0.041

MetaRNN

Uncertain

0.69

D;D

MetaSVM

Benign

-0.64

MutationAssessor

Benign

1.8

.;L

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.8

N;N

REVEL

Uncertain

0.33

Sift

Uncertain

0.014

D;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

1.0

D;D

Vest4

0.58

MutPred

0.28

.;Loss of phosphorylation at S348 (P = 7e-04);

MVP

0.78

MPC

0.53

ClinPred

0.95

GERP RS

4.8

Varity_R

0.28

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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