3-32954384-C-T

Variant names:

• chr3-32954384-C-T
• NM_005508.5:c.962C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005508.5(CCR4):​c.962C>T​(p.Thr321Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CCR4 NM_005508.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.06
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13401493).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005508.5. 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
	CCR4	NM_005508.5	MANE Select	c.962C>T	p.Thr321Ile	missense	Exon 2 of 2	NP_005499.1	P51679

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCR4	ENST00000330953.6	TSL:1 MANE Select	c.962C>T	p.Thr321Ile	missense	Exon 2 of 2	ENSP00000332659.5	P51679
	CCR4	ENST00000718415.1		c.962C>T	p.Thr321Ile	missense	Exon 2 of 2	ENSP00000520802.1	P51679

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460980 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726782

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33410

American (AMR) AF: 0.00 AC: 0 AN: 44550

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86072

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111706

Other (OTH) AF: 0.00 AC: 0 AN: 60338

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0448430), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

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	0.14
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.084
Eigen_PC	Benign	0.053
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.1
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.13
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.033	D
Polyphen		0.0040	B
Vest4		0.28
MutPred		0.55		Gain of ubiquitination at K320 (P = 0.0497)
MVP		0.28
MPC		0.32
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.10
gMVP		0.26
Mutation Taster		=89/11	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

hg19: chr3-32995876;