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GeneBe

4-76022790-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001565.4(CXCL10):c.89G>A(p.Cys30Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,611,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CXCL10
NM_001565.4 missense

Scores

7
8
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.77
Variant links:
Genes affected
CXCL10 (HGNC:10637): (C-X-C motif chemokine ligand 10) This antimicrobial gene encodes a chemokine of the CXC subfamily and ligand for the receptor CXCR3. Binding of this protein to CXCR3 results in pleiotropic effects, including stimulation of monocytes, natural killer and T-cell migration, and modulation of adhesion molecule expression. This gene may also be a key regulator of the 'cytokine storm' immune response to SARS-CoV-2 infection. [provided by RefSeq, Sep 2020]
ART3 (HGNC:725): (ADP-ribosyltransferase 3 (inactive)) This gene encodes an arginine-specific ADP-ribosyltransferase. The encoded protein catalyzes a reversible reaction which modifies proteins by the addition or removal of ADP-ribose to an arginine residue to regulate the function of the modified protein. An ADP-ribosyltransferase pseudogene is located on chromosome 11. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

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ACMG classification

Classification made for transcript

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, 0.993

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CXCL10NM_001565.4 linkuse as main transcriptc.89G>A p.Cys30Tyr missense_variant 2/4 ENST00000306602.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CXCL10ENST00000306602.3 linkuse as main transcriptc.89G>A p.Cys30Tyr missense_variant 2/41 NM_001565.4 P1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152136
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1459732
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726286
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152254
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74446
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 21, 2022The c.89G>A (p.C30Y) alteration is located in exon 2 (coding exon 2) of the CXCL10 gene. This alteration results from a G to A substitution at nucleotide position 89, causing the cysteine (C) at amino acid position 30 to be replaced by a tyrosine (Y). 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
0.86
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.15
Cadd
Uncertain
25
Dann
Uncertain
0.99
DEOGEN2
Uncertain
0.48
T
Eigen
Uncertain
0.47
Eigen_PC
Uncertain
0.41
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Benign
0.78
T
M_CAP
Uncertain
0.24
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Benign
-0.44
T
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.62
T
PROVEAN
Pathogenic
-11
D
REVEL
Uncertain
0.53
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.89
MutPred
0.93
Loss of sheet (P = 0.0817);
MVP
0.65
MPC
0.63
ClinPred
1.0
D
GERP RS
4.9
Varity_R
0.95
gMVP
0.95

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: rs201830102; hg19: chr4-76943943; API