NM_001504.2:c.925A>G

Variant names:

• chrX-71616547-T-C
• rs766079896
• NM_001504.2:c.925A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001504.2(CXCR3):​c.925A>G​(p.Met309Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,097,126 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M309L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: CXCR3 NM_001504.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.27
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.098959416).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001504.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXCR3	NM_001504.2	MANE Select	c.925A>G	p.Met309Val	missense	Exon 2 of 2	NP_001495.1	P49682-1
	CXCR3	NM_001142797.2		c.1066A>G	p.Met356Val	missense	Exon 2 of 2	NP_001136269.1	P49682-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXCR3	ENST00000373693.4	TSL:1 MANE Select	c.925A>G	p.Met309Val	missense	Exon 2 of 2	ENSP00000362797.3	P49682-1
	CXCR3	ENST00000373691.4	TSL:1	c.1066A>G	p.Met356Val	missense	Exon 2 of 2	ENSP00000362795.4	P49682-2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000110 AC: 2 AN: 181924 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000246

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097126 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 362564

African (AFR) AF: 0.00 AC: 0 AN: 26385

American (AMR) AF: 0.00 AC: 0 AN: 35144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19336

East Asian (EAS) AF: 0.00 AC: 0 AN: 30182

South Asian (SAS) AF: 0.00 AC: 0 AN: 53999

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40495

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4131

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 841410

Other (OTH) AF: 0.00 AC: 0 AN: 46044

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	9.2
DANN	Benign	0.90
DEOGEN2	Benign	0.13	T
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.099	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.93	N
PhyloP100		-1.3
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.052
Sift	Benign	0.71	T
Sift4G	Benign	0.32	T
Polyphen		0.0090	B
Vest4		0.14
MutPred		0.40		Loss of catalytic residue at M309 (P = 0.0871)
MVP		0.86
MPC		0.74
ClinPred		0.049	T
GERP RS		2.7
Varity_R		0.061
gMVP		0.41
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs766079896; hg19: chrX-70836397;