NM_001504.2:c.341C>A

Variant names:

• chrX-71617131-G-T
• rs1205329454
• NM_001504.2:c.341C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001504.2(CXCR3):​c.341C>A​(p.Ala114Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CXCR3 NM_001504.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.64

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CXCR3	NM_001504.2	c.341C>A	p.Ala114Asp	missense_variant	Exon 2 of 2	ENST00000373693.4	NP_001495.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CXCR3	ENST00000373693.4	c.341C>A	p.Ala114Asp	missense_variant	Exon 2 of 2	1	NM_001504.2	ENSP00000362797.3
CXCR3	ENST00000373691.4	c.482C>A	p.Ala161Asp	missense_variant	Exon 2 of 2	1		ENSP00000362795.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000579 AC: 1 AN: 172730 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 59526

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000749

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.482C>A (p.A161D) alteration is located in exon 2 (coding exon 1) of the CXCR3 gene. This alteration results from a C to A substitution at nucleotide position 482, causing the alanine (A) at amino acid position 161 to be replaced by an aspartic acid (D). 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	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.39	.;T
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.4	.;M
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		0.88	P;D
Vest4		0.81
MutPred		0.73		.;Gain of relative solvent accessibility (P = 0.0479);
MVP		0.61
MPC		2.2
ClinPred		0.82	D
GERP RS		4.6
Varity_R		0.71
gMVP		0.86

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

Other links and lift over

dbSNP: rs1205329454; hg19: chrX-70836981;