Genetic Variant CCR3:p.Pro39Leu (chr3-46265274-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_178329.3(CCR3):c.116C>T(p.Pro39Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00349 in 1,614,032 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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 0.0058 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0033 ( 26 hom. )

Consequence

CCR3
NM_178329.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0310

Publications

20 publications found

Variant links:

Genes affected

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]

CCR3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012571186).

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00326 (4760/1461762) while in subpopulation MID AF = 0.018 (104/5768). AF 95% confidence interval is 0.0152. There are 26 homozygotes in GnomAdExome4. There are 2411 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCR3	NM_178329.3 link	c.116C>T	p.Pro39Leu	missense_variant	Exon 2 of 2	ENST00000395940.3	NP_847899.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCR3	ENST00000395940.3 link	c.116C>T	p.Pro39Leu	missense_variant	Exon 2 of 2	1	NM_178329.3	ENSP00000379271.2

Frequencies

GnomAD3 genomes

AF:

0.00578

AC:

879

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0105

Gnomad ASJ

AF:

0.0176

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.00273

Gnomad OTH

AF:

0.00959

GnomAD2 exomes

AF:

0.00383

AC:

962

AN:

250988

AF XY:

0.00372

show subpopulations

Gnomad AFR exome

AF:

0.00892

Gnomad AMR exome

AF:

0.00663

Gnomad ASJ exome

AF:

0.0159

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.000416

Gnomad NFE exome

AF:

0.00320

Gnomad OTH exome

AF:

0.00785

GnomAD4 exome

AF:

0.00326

AC:

4760

AN:

1461762

Hom.:

Cov.:

AF XY:

0.00332

AC XY:

2411

AN XY:

727184

show subpopulations

African (AFR)

AF:

0.0124

AC:

415

AN:

33474

American (AMR)

AF:

0.00725

AC:

324

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0167

AC:

436

AN:

26132

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39650

South Asian (SAS)

AF:

0.000278

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000393

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.0180

AC:

104

AN:

5768

European-Non Finnish (NFE)

AF:

0.00272

AC:

3024

AN:

1111974

Other (OTH)

AF:

0.00679

AC:

410

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

281

562

844

1125

1406

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

248

372

496

620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00577

AC:

878

AN:

152270

Hom.:

Cov.:

AF XY:

0.00549

AC XY:

409

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0104

AC:

432

AN:

41548

American (AMR)

AF:

0.0105

AC:

161

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0176

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.000622

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00273

AC:

186

AN:

68024

Other (OTH)

AF:

0.00949

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

137

182

228

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00408

Hom.:

Bravo

AF:

0.00729

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00931

AC:

ESP6500EA

AF:

0.00372

AC:

ExAC

AF:

0.00366

AC:

444

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.00458

EpiControl

AF:

0.00504

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

T;.;T;.;T

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.0

.;T;.;T;T

MetaRNN

Benign

0.013

T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.6

L;.;L;.;L

PhyloP100

-0.031

PrimateAI

Benign

0.34

PROVEAN

Pathogenic

-7.7

D;D;D;D;D

REVEL

Benign

0.14

Sift

Uncertain

0.013

D;D;D;D;D

Sift4G

Benign

0.36

T;T;T;T;T

Vest4

0.048

ClinPred

0.058

GERP RS

5.2

PromoterAI

0.022

Neutral

(source)

Varity_R

0.18

gMVP

0.41

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over