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GeneBe

16-57382433-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002996.6(CX3CL1):c.595A>G(p.Ser199Gly) 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 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: not found (cov: 32)

Consequence

CX3CL1
NM_002996.6 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.378
Variant links:
Genes affected
CX3CL1 (HGNC:10647): (C-X3-C motif chemokine ligand 1) This gene belongs to the CX3C subgroup of chemokines, characterized by the number of amino acids located between the conserved cysteine residues. This is the only member of the CX3C subgroup, which contains three amino acids between cysteine residues, resulting in a Cys-X-X-X-Cys configuration. The encoded protein contains an extended mucin-like stalk with a chemokine domain on top, and exists in both a membrane-anchored form where it acts as a binding molecule, or, in soluble form, as a chemotactic cytokine. The mature form of this protein can be cleaved at the cell surface, yielding different soluble forms that can interact with the G-protein coupled receptor, C-X3-C motif chemokine receptor 1 gene product. This gene plays a role in a wide range of diseases, including cancer, vasculitis, neuropathies, atherosclerosis, inflammatory diseases, and in human immunodeficiency virus infections. [provided by RefSeq, Sep 2017]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.0651412).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CX3CL1NM_002996.6 linkuse as main transcriptc.595A>G p.Ser199Gly missense_variant 3/3 ENST00000006053.7
CX3CL1NM_001304392.3 linkuse as main transcriptc.340A>G p.Ser114Gly missense_variant 2/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CX3CL1ENST00000006053.7 linkuse as main transcriptc.595A>G p.Ser199Gly missense_variant 3/31 NM_002996.6 P4
CX3CL1ENST00000565912.1 linkuse as main transcriptc.481A>G p.Ser161Gly missense_variant 2/21
CX3CL1ENST00000563383.1 linkuse as main transcriptc.613A>G p.Ser205Gly missense_variant 3/35 A2
CX3CL1ENST00000564948.1 linkuse as main transcriptc.*306A>G 3_prime_UTR_variant 2/23

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

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 GeneticsAug 30, 2022The c.595A>G (p.S199G) alteration is located in exon 3 (coding exon 3) of the CX3CL1 gene. This alteration results from a A to G substitution at nucleotide position 595, causing the serine (S) at amino acid position 199 to be replaced by a glycine (G). 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
0.081
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.69
Cadd
Benign
14
Dann
Uncertain
0.98
DEOGEN2
Benign
0.41
T;T;.
Eigen
Benign
-0.73
Eigen_PC
Benign
-0.71
FATHMM_MKL
Benign
0.15
N
LIST_S2
Benign
0.46
T;T;T
M_CAP
Benign
0.0032
T
MetaRNN
Benign
0.065
T;T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
1.5
L;.;.
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-1.6
N;N;.
REVEL
Benign
0.070
Sift
Uncertain
0.0070
D;D;.
Sift4G
Uncertain
0.018
D;D;D
Polyphen
0.014
B;.;.
Vest4
0.081
MutPred
0.30
Loss of glycosylation at S199 (P = 0.006);.;.;
MVP
0.068
MPC
0.28
ClinPred
0.26
T
GERP RS
1.8
Varity_R
0.23
gMVP
0.19

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: rs368270552; hg19: chr16-57416345; API