NM_001504.2:c.217G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001504.2(CXCR3):​c.217G>A​(p.Ala73Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000585 in 1,196,112 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)
Exomes 𝑓: 0.0000055 ( 0 hom. 1 hem. )

Consequence

CXCR3
NM_001504.2 missense

Scores

3
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0950
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.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.17308182).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CXCR3NM_001504.2 linkc.217G>A p.Ala73Thr missense_variant Exon 2 of 2 ENST00000373693.4 NP_001495.1 P49682-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CXCR3ENST00000373693.4 linkc.217G>A p.Ala73Thr missense_variant Exon 2 of 2 1 NM_001504.2 ENSP00000362797.3 P49682-1
CXCR3ENST00000373691.4 linkc.358G>A p.Ala120Thr missense_variant Exon 2 of 2 1 ENSP00000362795.4 P49682-2

Frequencies

GnomAD3 genomes
AF:
0.00000892
AC:
1
AN:
112056
Hom.:
0
Cov.:
23
AF XY:
0.00
AC XY:
0
AN XY:
34226
show subpopulations
Gnomad AFR
AF:
0.0000324
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000132
AC:
2
AN:
150950
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
45932
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:
0.0000311
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000553
AC:
6
AN:
1084056
Hom.:
0
Cov.:
32
AF XY:
0.00000283
AC XY:
1
AN XY:
353202
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.00000599
Gnomad4 OTH exome
AF:
0.0000219
GnomAD4 genome
AF:
0.00000892
AC:
1
AN:
112056
Hom.:
0
Cov.:
23
AF XY:
0.00
AC XY:
0
AN XY:
34226
show subpopulations
Gnomad4 AFR
AF:
0.0000324
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:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.00000831
AC:
1

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Nov 11, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.358G>A (p.A120T) alteration is located in exon 2 (coding exon 1) of the CXCR3 gene. This alteration results from a G to A substitution at nucleotide position 358, causing the alanine (A) at amino acid position 120 to be replaced by a threonine (T). 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
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.61
CADD
Benign
1.1
DANN
Benign
0.97
DEOGEN2
Benign
0.15
.;T
FATHMM_MKL
Benign
0.22
N
LIST_S2
Benign
0.51
T;T
M_CAP
Uncertain
0.094
D
MetaRNN
Benign
0.17
T;T
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
0.56
.;N
PrimateAI
Uncertain
0.50
T
PROVEAN
Benign
-0.43
N;N
REVEL
Benign
0.087
Sift
Benign
0.071
T;T
Sift4G
Uncertain
0.011
D;D
Polyphen
0.010
B;B
Vest4
0.083
MVP
0.76
MPC
0.71
ClinPred
0.051
T
GERP RS
2.8
Varity_R
0.045
gMVP
0.54

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: rs747049805; hg19: chrX-70837105; COSMIC: COSV101031686; COSMIC: COSV101031686; API