3-46370444-A-G

Variant names:

• chr3-46370444-A-G
• rs1799987
• ENST00000451485.3:n.572+800T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000579.4(CCR5):​c.-301+246A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.491 in 151,794 control chromosomes in the GnomAD database, including 18,573 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,protective (no stars).

• Frequency: Genomes: 𝑓 0.49 (18573 hom., cov: 30)
• Consequence: CCR5 NM_000579.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity; protective no assertion criteria provided P:1 B:3
• Conservation: PhyloP100: -0.587
• Publications: 125 publications found

Genes affected

CCR5AS (HGNC:54398): (CCR5 antisense RNA)

CCR5 (HGNC:1606): (C-C motif chemokine receptor 5) 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. This protein is expressed by T cells and macrophages, and is known to be an important co-receptor for macrophage-tropic virus, including HIV, to enter host cells. Defective alleles of this gene have been associated with the HIV infection resistance. The ligands of this receptor include monocyte chemoattractant protein 2 (MCP-2), macrophage inflammatory protein 1 alpha (MIP-1 alpha), macrophage inflammatory protein 1 beta (MIP-1 beta) and regulated on activation normal T expressed and secreted protein (RANTES). Expression of this gene was also detected in a promyeloblastic cell line, suggesting that this protein may play a role in granulocyte lineage proliferation and differentiation. This gene is located at the chemokine receptor gene cluster region. An allelic polymorphism in this gene results in both functional and non-functional alleles; the reference genome represents the functional allele. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2015]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.593 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000579.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCR5AS	NR_125406.2	MANE Select	n.572+800T>C		intron	N/A
	CCR5	NM_000579.4		c.-301+246A>G		intron	N/A	NP_000570.1
	CCR5	NM_001100168.2		c.-66+246A>G		intron	N/A	NP_001093638.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCR5AS	ENST00000451485.3	TSL:3 MANE Select	n.572+800T>C		intron	N/A
	CCR5AS	ENST00000701879.2		n.462+800T>C		intron	N/A
	CCR5AS	ENST00000717843.1		n.324+800T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.491 AC: 74529 AN: 151674 Hom.: 18552 Cov.: 30

Gnomad AFR AF: 0.571

Gnomad AMI AF: 0.466

Gnomad AMR AF: 0.460

Gnomad ASJ AF: 0.444

Gnomad EAS AF: 0.589

Gnomad SAS AF: 0.610

Gnomad FIN AF: 0.460

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.441

Gnomad OTH AF: 0.496

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.491 AC: 74586 AN: 151794 Hom.: 18573 Cov.: 30 AF XY: 0.496 AC XY: 36779 AN XY: 74166

African (AFR) AF: 0.571 AC: 23616 AN: 41378

American (AMR) AF: 0.460 AC: 7025 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.444 AC: 1536 AN: 3460

East Asian (EAS) AF: 0.588 AC: 3031 AN: 5152

South Asian (SAS) AF: 0.612 AC: 2948 AN: 4820

European-Finnish (FIN) AF: 0.460 AC: 4828 AN: 10492

Middle Eastern (MID) AF: 0.568 AC: 166 AN: 292

European-Non Finnish (NFE) AF: 0.441 AC: 29973 AN: 67914

Other (OTH) AF: 0.492 AC: 1039 AN: 2112

Alfa AF: 0.479 Hom.: 10928

Bravo AF: 0.493

Asia WGS AF: 0.535 AC: 1859 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity; protective

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Acquired immunodeficiency syndrome, delayed progression to (1)
-	-	1	CCR5 PROMOTER POLYMORPHISM (1)
-	-	1	CCR5-related disorder (1)
-	-	-	Susceptibility to HIV infection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.98
DANN	Benign	0.40
PhyloP100		-0.59
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1799987; hg19: chr3-46411935;