16-57382433-A-G

Position:

• chr16-57382433-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_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. 14/21 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.378

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]

ACMG classification

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	Protein	UniProt
CX3CL1	NM_002996.6	c.595A>G	p.Ser199Gly	missense_variant	3/3	ENST00000006053.7	NP_002987.1
CX3CL1	NM_001304392.3	c.340A>G	p.Ser114Gly	missense_variant	2/2		NP_001291321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CX3CL1	ENST00000006053.7	c.595A>G	p.Ser199Gly	missense_variant	3/3	1	NM_002996.6	ENSP00000006053.6
CX3CL1	ENST00000565912.1	c.481A>G	p.Ser161Gly	missense_variant	2/2	1		ENSP00000464114.1
CX3CL1	ENST00000563383.1	c.613A>G	p.Ser205Gly	missense_variant	3/3	5		ENSP00000456830.1
CX3CL1	ENST00000564948.1	c.*306A>G		3_prime_UTR_variant	2/2	3		ENSP00000457996.1

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

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2022

The 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;.;.
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

Other links and lift over

dbSNP: rs368270552; hg19: chr16-57416345;