Genetic Variant CX3CL1:p.Pro140Leu (chr16-57382257-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

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

The NM_002996.6(CX3CL1):c.419C>T(p.Pro140Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000559 in 1,609,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

CX3CL1
NM_002996.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.40

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]

CX3CL1 links:

Genome browser will be placed here

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=0.031294584).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CX3CL1	NM_002996.6 link	c.419C>T	p.Pro140Leu	missense_variant	Exon 3 of 3	ENST00000006053.7	NP_002987.1	P78423A0N0N7
CX3CL1	NM_001304392.3 link	c.164C>T	p.Pro55Leu	missense_variant	Exon 2 of 2		NP_001291321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CX3CL1	ENST00000006053.7 link	c.419C>T	p.Pro140Leu	missense_variant	Exon 3 of 3	1	NM_002996.6	ENSP00000006053.6	P78423
CX3CL1	ENST00000565912.1 link	c.305C>T	p.Pro102Leu	missense_variant	Exon 2 of 2	1		ENSP00000464114.1	J3QRA1
CX3CL1	ENST00000563383.1 link	c.437C>T	p.Pro146Leu	missense_variant	Exon 3 of 3	5		ENSP00000456830.1	H3BSR6
CX3CL1	ENST00000564948.1 link	c.*130C>T		3_prime_UTR_variant	Exon 2 of 2	3		ENSP00000457996.1	H3BV86

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00000406

AC:

AN:

246040

Hom.:

AF XY:

0.00

AC XY:

AN XY:

133972

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:

0.00000907

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000549

AC:

AN:

1457390

Hom.:

Cov.:

AF XY:

0.00000967

AC XY:

AN XY:

724258

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000451

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

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

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.066

DANN

Benign

0.62

DEOGEN2

Benign

0.25

T;T;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0026

LIST_S2

Benign

0.45

T;T;T

M_CAP

Benign

0.0046

MetaRNN

Benign

0.031

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.20

N;.;.

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.0

N;N;.

REVEL

Benign

0.063

Sift

Benign

1.0

T;T;.

Sift4G

Benign

0.38

T;T;T

Polyphen

0.0020

B;.;.

Vest4

0.042

MutPred

0.25

Loss of helix (P = 3e-04);.;.;

MVP

0.043

MPC

0.31

ClinPred

0.025

GERP RS

-7.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.026

gMVP

0.22

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over