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GeneBe

16-57372636-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_002996.6(CX3CL1):c.68C>A(p.Ala23Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

CX3CL1
NM_002996.6 missense, splice_region

Scores

1
8
10
Splicing: ADA: 0.1807
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.926
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 Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.2907795).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CX3CL1NM_002996.6 linkuse as main transcriptc.68C>A p.Ala23Asp missense_variant, splice_region_variant 1/3 ENST00000006053.7
CX3CL1NM_001304392.3 linkuse as main transcriptc.-67C>A splice_region_variant, 5_prime_UTR_variant 1/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CX3CL1ENST00000006053.7 linkuse as main transcriptc.68C>A p.Ala23Asp missense_variant, splice_region_variant 1/31 NM_002996.6 P4
CX3CL1ENST00000563383.1 linkuse as main transcriptc.68C>A p.Ala23Asp missense_variant, splice_region_variant 1/35 A2
CX3CL1ENST00000564948.1 linkuse as main transcriptc.68C>A p.Ala23Asp missense_variant, splice_region_variant 1/23

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
250818
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135618
show subpopulations
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000616
AC:
9
AN:
1461318
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
726974
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:
0.00000719
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

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 GeneticsFeb 28, 2023The c.68C>A (p.A23D) alteration is located in exon 1 (coding exon 1) of the CX3CL1 gene. This alteration results from a C to A substitution at nucleotide position 68, causing the alanine (A) at amino acid position 23 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
0.65
BayesDel_addAF
Benign
-0.058
T
BayesDel_noAF
Benign
-0.21
Cadd
Benign
18
Dann
Uncertain
0.99
DEOGEN2
Uncertain
0.56
D;T;.
Eigen
Benign
-0.36
Eigen_PC
Benign
-0.49
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Benign
0.54
T;T;T
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.28
T;T;T
MetaSVM
Benign
-0.95
T
MutationAssessor
Uncertain
2.2
M;.;.
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Uncertain
0.52
T
PROVEAN
Uncertain
-2.8
D;D;D
REVEL
Benign
0.18
Sift
Uncertain
0.0070
D;D;.
Sift4G
Uncertain
0.056
T;D;D
Polyphen
0.93
P;.;.
Vest4
0.63
MutPred
0.41
Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);
MVP
0.17
MPC
0.98
ClinPred
0.82
D
GERP RS
2.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.26
gMVP
0.81

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.18
dbscSNV1_RF
Benign
0.50
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: rs773579770; hg19: chr16-57406548; API