NM_002996.6:c.515C>T

Variant names:

• chr16-57382353-C-T
• rs199869986
• NM_002996.6:c.515C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002996.6(CX3CL1):​c.515C>T​(p.Thr172Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00024 in 1,609,802 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (3 hom.)
• Consequence: CX3CL1 NM_002996.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.758
• Publications: 4 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005621642).
• BS2: High Homozygotes in GnomAdExome4 at 3 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002996.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CX3CL1	NM_002996.6	MANE Select	c.515C>T	p.Thr172Met	missense	Exon 3 of 3	NP_002987.1	P78423
	CX3CL1	NM_001304392.3		c.260C>T	p.Thr87Met	missense	Exon 2 of 2	NP_001291321.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CX3CL1	ENST00000006053.7	TSL:1 MANE Select	c.515C>T	p.Thr172Met	missense	Exon 3 of 3	ENSP00000006053.6	P78423
	CX3CL1	ENST00000565912.1	TSL:1	c.401C>T	p.Thr134Met	missense	Exon 2 of 2	ENSP00000464114.1	J3QRA1
	CX3CL1	ENST00000563383.1	TSL:5	c.533C>T	p.Thr178Met	missense	Exon 3 of 3	ENSP00000456830.1	H3BSR6

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000360 AC: 88 AN: 244448 AF XY: 0.000330

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000204

Gnomad ASJ exome AF: 0.00616

Gnomad EAS exome AF: 0.000330

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000996

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000233 AC: 340 AN: 1457502 Hom.: 3 Cov.: 31 AF XY: 0.000223 AC XY: 162 AN XY: 725066

African (AFR) AF: 0.0000897 AC: 3 AN: 33448

American (AMR) AF: 0.000247 AC: 11 AN: 44590

Ashkenazi Jewish (ASJ) AF: 0.00752 AC: 196 AN: 26078

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39648

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86018

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50210

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.0000639 AC: 71 AN: 1111424

Other (OTH) AF: 0.000845 AC: 51 AN: 60320

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74474

African (AFR) AF: 0.00 AC: 0 AN: 41572

American (AMR) AF: 0.000261 AC: 4 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00836 AC: 29 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000429 Hom.: 1

Bravo AF: 0.000257

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.76
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.073
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.20
MVP		0.043
MPC		0.88
ClinPred		0.085	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.28
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs199869986; hg19: chr16-57416265; COSMIC: COSV99076814;