Genetic Variant CXCR3:p.Lys27Glu (chrX-71617534-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_001142797.2(CXCR3):c.79A>G(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 (★).

Frequency

Genomes: 𝑓 0.0000091 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.0000038 ( 0 hom. 4 hem. )

Failed GnomAD Quality Control

Consequence

CXCR3
NM_001142797.2 missense

Scores

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]

CXCR3 links:

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
CXCR3	NM_001504.2 link	c.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
CXCR3	ENST00000373691.4 link	c.79A>G	p.Lys27Glu	missense_variant	Exon 2 of 2	1		ENSP00000362795.4		P49682-2
CXCR3	ENST00000373693.4 link	c.13-75A>G		intron_variant	Intron 1 of 1	1	NM_001504.2	ENSP00000362797.3		P49682-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

110391

Hom.:

Cov.:

AF XY:

0.0000306

AC XY:

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:

AN:

122990

Hom.:

AF XY:

0.000102

AC XY:

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:

AN:

1063895

Hom.:

Cov.:

AF XY:

0.0000116

AC XY:

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:

AN:

110391

Hom.:

Cov.:

AF XY:

0.0000306

AC XY:

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

BayesDel_noAF

Benign

-0.64

CADD

Benign

4.8

DANN

Benign

0.76

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.21

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.82

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.16

REVEL

Benign

0.11

Sift

Benign

0.10

Polyphen

0.59

Vest4

0.19

MutPred

0.15

Loss of ubiquitination at K27 (P = 0.0027);

MVP

0.53

MPC

1.0

ClinPred

0.12

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.

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