Genetic Variant NM_002996.6:c.32G>A (chr16-57372600-G-A) – 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.32G>A(p.Arg11His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,613,390 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.00081 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000086 ( 1 hom. )

Consequence

CX3CL1
NM_002996.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.678

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:

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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=0.006783217).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CX3CL1	NM_002996.6 link	c.32G>A	p.Arg11His	missense_variant	Exon 1 of 3	ENST00000006053.7	NP_002987.1	P78423A0N0N7
CX3CL1	NM_001304392.3 link	c.-103G>A		5_prime_UTR_variant	Exon 1 of 2		NP_001291321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CX3CL1	ENST00000006053.7 link	c.32G>A	p.Arg11His	missense_variant	Exon 1 of 3	1	NM_002996.6	ENSP00000006053.6	P78423
CX3CL1	ENST00000563383.1 link	c.32G>A	p.Arg11His	missense_variant	Exon 1 of 3	5		ENSP00000456830.1	H3BSR6
CX3CL1	ENST00000564948.1 link	c.32G>A	p.Arg11His	missense_variant	Exon 1 of 2	3		ENSP00000457996.1	H3BV86

Frequencies

GnomAD3 genomes

AF:

0.000815

AC:

124

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00220

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

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:

0.00

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000144

AC:

AN:

250614

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135544

show subpopulations

Gnomad AFR exome

AF:

0.00179

Gnomad AMR exome

AF:

0.0000868

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:

0.00000881

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.0000856

AC:

125

AN:

1461106

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

726892

show subpopulations

Gnomad4 AFR exome

AF:

0.00251

Gnomad4 AMR exome

AF:

0.000157

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:

0.0000117

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000814

AC:

124

AN:

152284

Hom.:

Cov.:

AF XY:

0.000833

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00219

Gnomad4 AMR

AF:

0.00190

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000191

Hom.:

Bravo

AF:

0.000945

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000165

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.37

T;T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.63

T;T;T

M_CAP

Benign

0.0032

MetaRNN

Benign

0.0068

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.0

L;.;.

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.7

N;N;D

REVEL

Benign

0.037

Sift

Benign

0.32

T;T;.

Sift4G

Benign

0.43

T;T;D

Polyphen

0.0020

B;.;.

Vest4

0.053

MVP

0.13

MPC

0.37

ClinPred

0.0099

GERP RS

-0.030

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.044

gMVP

0.55

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