X-71617534-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4_Moderate

The NM_001142797.2(CXCR3):ā€‹c.79A>Gā€‹(p.Lys27Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000091 ( 0 hom., 1 hem., cov: 22)
Exomes š‘“: 0.0000038 ( 0 hom. 4 hem. )
Failed GnomAD Quality Control

Consequence

CXCR3
NM_001142797.2 missense

Scores

1
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.41
Variant links:
Genes affected
CXCR3 (HGNC:4540): (C-X-C motif chemokine receptor 3) This gene encodes a G protein-coupled receptor with selectivity for three chemokines, termed CXCL9/Mig (monokine induced by interferon-g), CXCL10/IP10 (interferon-g-inducible 10 kDa protein) and CXCL11/I-TAC (interferon-inducible T cell a-chemoattractant). Binding of chemokines to this protein induces cellular responses that are involved in leukocyte traffic, most notably integrin activation, cytoskeletal changes and chemotactic migration. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. One of the isoforms (CXCR3-B) shows high affinity binding to chemokine, CXCL4/PF4 (PMID:12782716). [provided by RefSeq, Jun 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1
In a mutagenesis_site Reduces sulfation and CXCL9-, CXCL10- and CXCL11-induced chemotaxis. Abolishes binding to CXCL10. Abolishes sulfation, binding to CXCL11, ligand-induced receptor internalization and CXCL9-, CXCL10- and CXCL11-induced chemotaxis; when associated with F-29. (size 0) in uniprot entity CXCR3_HUMAN
BP4
Computational evidence support a benign effect (MetaRNN=0.16315302).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CXCR3NM_001504.2 linkc.13-75A>G intron_variant Intron 1 of 1 ENST00000373693.4 NP_001495.1 P49682-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CXCR3ENST00000373691.4 linkc.79A>G p.Lys27Glu missense_variant Exon 2 of 2 1 ENSP00000362795.4 P49682-2
CXCR3ENST00000373693.4 linkc.13-75A>G intron_variant Intron 1 of 1 1 NM_001504.2 ENSP00000362797.3 P49682-1

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
1
AN:
110391
Hom.:
0
Cov.:
22
AF XY:
0.0000306
AC XY:
1
AN XY:
32643
FAILED QC
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000957
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000325
AC:
4
AN:
122990
Hom.:
0
AF XY:
0.000102
AC XY:
4
AN XY:
39320
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000147
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:
0.00
Gnomad OTH exome
AF:
0.000291
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000376
AC:
4
AN:
1063895
Hom.:
0
Cov.:
31
AF XY:
0.0000116
AC XY:
4
AN XY:
344813
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000102
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:
0.0000223
GnomAD4 genome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000906
AC:
1
AN:
110391
Hom.:
0
Cov.:
22
AF XY:
0.0000306
AC XY:
1
AN XY:
32643
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000957
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000227

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 28, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.79A>G (p.K27E) alteration is located in exon 2 (coding exon 1) of the CXCR3 gene. This alteration results from a A to G substitution at nucleotide position 79, causing the lysine (K) at amino acid position 27 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.64
CADD
Benign
4.8
DANN
Benign
0.76
FATHMM_MKL
Benign
0.18
N
LIST_S2
Benign
0.21
T
M_CAP
Uncertain
0.091
D
MetaRNN
Benign
0.16
T
MetaSVM
Benign
-0.82
T
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-0.16
N
REVEL
Benign
0.11
Sift
Benign
0.10
T
Polyphen
0.59
P
Vest4
0.19
MutPred
0.15
Loss of ubiquitination at K27 (P = 0.0027);
MVP
0.53
MPC
1.0
ClinPred
0.12
T
GERP RS
0.23
gMVP
0.21

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.

Other links and lift over

dbSNP: rs1407520700; hg19: chrX-70837384; API