3-46203838-G-A

Position:

• chr3-46203838-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001295.3(CCR1):​c.476C>T​(p.Ala159Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,614,182 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (5 hom.)
• Consequence: CCR1 NM_001295.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.37

Genes affected

CCR1 (HGNC:1602): (C-C motif chemokine receptor 1) This gene encodes a member of the beta chemokine receptor family, which is predicted to be a seven transmembrane protein similar to G protein-coupled receptors. The ligands of this receptor include macrophage inflammatory protein 1 alpha (MIP-1 alpha), regulated on activation normal T expressed and secreted protein (RANTES), monocyte chemoattractant protein 3 (MCP-3), and myeloid progenitor inhibitory factor-1 (MPIF-1). Chemokines and their receptors mediated signal transduction are critical for the recruitment of effector immune cells to the site of inflammation. Knockout studies of the mouse homolog suggested the roles of this gene in host protection from inflammatory response, and susceptibility to virus and parasite. This gene and other chemokine receptor genes, including CCR2, CCRL2, CCR3, CCR5 and CCXCR1, are found to form a gene cluster on chromosome 3p. [provided by RefSeq, Jul 2008]

CCR3 (HGNC:1604): (C-C motif chemokine receptor 3) The protein encoded by this gene is a receptor for C-C type chemokines. It belongs to family 1 of the G protein-coupled receptors. This receptor binds and responds to a variety of chemokines, including eotaxin (CCL11), eotaxin-3 (CCL26), MCP-3 (CCL7), MCP-4 (CCL13), and RANTES (CCL5). It is highly expressed in eosinophils and basophils, and is also detected in TH1 and TH2 cells, as well as in airway epithelial cells. This receptor may contribute to the accumulation and activation of eosinophils and other inflammatory cells in the allergic airway. It is also known to be an entry co-receptor for HIV-1. This gene and seven other chemokine receptor genes form a chemokine receptor gene cluster on the chromosomal region 3p21. Alternatively spliced transcript variants have been described. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008763075).
• BP6: Variant 3-46203838-G-A is Benign according to our data. Variant chr3-46203838-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 713779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCR1	NM_001295.3	c.476C>T	p.Ala159Val	missense_variant	2/2	ENST00000296140.4	NP_001286.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCR1	ENST00000296140.4	c.476C>T	p.Ala159Val	missense_variant	2/2	1	NM_001295.3	ENSP00000296140	P1
CCR3	ENST00000357422.2	c.-284-6853G>A		intron_variant		2		ENSP00000350003	P1

Frequencies

GnomAD3 genomes AF: 0.00243 AC: 370 AN: 152192 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00400

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00158 AC: 397 AN: 251284 Hom.: 0 AF XY: 0.00147 AC XY: 200 AN XY: 135788

Gnomad AFR exome AF: 0.00449

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.00894

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000986

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00112 AC: 1642 AN: 1461872 Hom.: 5 Cov.: 33 AF XY: 0.00107 AC XY: 778 AN XY: 727236

Gnomad4 AFR exome AF: 0.00481

Gnomad4 AMR exome AF: 0.00331

Gnomad4 ASJ exome AF: 0.00903

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000801

Gnomad4 OTH exome AF: 0.00283

GnomAD4 genome AF: 0.00243 AC: 370 AN: 152310 Hom.: 2 Cov.: 32 AF XY: 0.00212 AC XY: 158 AN XY: 74484

Gnomad4 AFR AF: 0.00399

Gnomad4 AMR AF: 0.00680

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00147 Hom.: 0

Bravo AF: 0.00345

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00144 AC: 175

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00136

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	CCR1: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 29, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.0010
DANN	Benign	0.87
DEOGEN2	Benign	0.047	T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.65	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.72	N
REVEL	Benign	0.053
Sift	Benign	1.0	T
Sift4G	Benign	0.92	T
Polyphen		0.0	B
Vest4		0.021
MVP		0.30
MPC		0.49
ClinPred		0.010	T
GERP RS		-9.7
Varity_R		0.018
gMVP		0.15

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: rs61752589; hg19: chr3-46245329;