chr3-32954167-G-A

Variant summary

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

The NM_005508.5(CCR4):​c.745G>A​(p.Val249Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,613,950 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

CCR4
NM_005508.5 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.49
Variant links:
Genes affected
CCR4 (HGNC:1605): (C-C motif chemokine receptor 4) The protein encoded by this gene belongs to the G-protein-coupled receptor family . It is a receptor for the CC chemokine - MIP-1, RANTES, TARC and MCP-1. Chemokines are a group of small polypeptide, structurally related molecules that regulate cell trafficking of various types of leukocytes. The chemokines also play fundamental roles in the development, homeostasis, and function of the immune system, and they have effects on cells of the central nervous system as well as on endothelial cells involved in angiogenesis or angiostasis. [provided by RefSeq, Jul 2008]

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=0.05141771).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CCR4NM_005508.5 linkuse as main transcriptc.745G>A p.Val249Ile missense_variant 2/2 ENST00000330953.6
CCR4XM_017005687.2 linkuse as main transcriptc.745G>A p.Val249Ile missense_variant 2/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CCR4ENST00000330953.6 linkuse as main transcriptc.745G>A p.Val249Ile missense_variant 2/21 NM_005508.5 P1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152076
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251364
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135862
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:
0.0000440
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000239
AC:
35
AN:
1461874
Hom.:
0
Cov.:
32
AF XY:
0.0000193
AC XY:
14
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000279
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152076
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74284
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 25, 2022The c.745G>A (p.V249I) alteration is located in exon 2 (coding exon 1) of the CCR4 gene. This alteration results from a G to A substitution at nucleotide position 745, causing the valine (V) at amino acid position 249 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.081
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.55
CADD
Benign
16
DANN
Benign
0.29
DEOGEN2
Benign
0.055
T
Eigen
Benign
-0.58
Eigen_PC
Benign
-0.31
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Benign
0.55
T
M_CAP
Benign
0.0022
T
MetaRNN
Benign
0.051
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.64
N
MutationTaster
Benign
0.78
N
PrimateAI
Benign
0.31
T
PROVEAN
Benign
0.54
N
REVEL
Benign
0.053
Sift
Benign
1.0
T
Sift4G
Benign
1.0
T
Polyphen
0.0010
B
Vest4
0.10
MutPred
0.51
Loss of catalytic residue at V249 (P = 0.003);
MVP
0.24
MPC
0.16
ClinPred
0.042
T
GERP RS
3.2
Varity_R
0.040
gMVP
0.13

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.

Other links and lift over

dbSNP: rs761144809; hg19: chr3-32995659; API