1-207575448-A-G

Variant names:

• chr1-207575448-A-G
• rs650877
• NM_000651.6:c.4452-147A>G

Variant summary

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

The NM_000651.6(CR1):​c.4452-147A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 973,324 control chromosomes in the GnomAD database, including 38,602 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.35 (13100 hom., cov: 33)
  • Exomes 𝑓: 0.22 (25502 hom.)
• Consequence: CR1 NM_000651.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.767
• Publications: 18 publications found

Genes affected

CR1 (HGNC:2334): (complement C3b/C4b receptor 1 (Knops blood group)) This gene is a member of the receptors of complement activation (RCA) family and is located in the 'cluster RCA' region of chromosome 1. The genome is polymorphic at this locus with allele-specific splice variants encoding different isoforms, based on the presence/absence of long homologous repeats (LHRs). The gene encodes a monomeric single-pass type I membrane glycoprotein found on erythrocytes, leukocytes, glomerular podocytes, and splenic follicular dendritic cells. The Knops blood group system is a system of antigens located on this protein. The protein mediates cellular binding to particles and immune complexes that have activated complement. Decreases in expression of this protein and/or mutations in this gene have been associated with gallbladder carcinomas, mesangiocapillary glomerulonephritis, systemic lupus erythematosus, sarcoidosis and Alzheimer's disease. Mutations in this gene have also been associated with a reduction in Plasmodium falciparum rosetting, conferring protection against severe malaria. [provided by RefSeq, May 2020]

CR1-AS1 (HGNC:40160):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.683 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CR1	NM_000651.6	c.4452-147A>G		intron_variant	Intron 27 of 46	ENST00000367049.9	NP_000642.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CR1	ENST00000367049.9	c.4452-147A>G		intron_variant	Intron 27 of 46	5	NM_000651.6	ENSP00000356016.4

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53540 AN: 152012 Hom.: 13073 Cov.: 33

Gnomad AFR AF: 0.690

Gnomad AMI AF: 0.251

Gnomad AMR AF: 0.322

Gnomad ASJ AF: 0.300

Gnomad EAS AF: 0.288

Gnomad SAS AF: 0.441

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.184

Gnomad OTH AF: 0.316

GnomAD4 exome AF: 0.223 AC: 182822 AN: 821194 Hom.: 25502 AF XY: 0.229 AC XY: 97453 AN XY: 426102

African (AFR) AF: 0.696 AC: 13735 AN: 19722

American (AMR) AF: 0.341 AC: 10222 AN: 29956

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 5575 AN: 18572

East Asian (EAS) AF: 0.248 AC: 8963 AN: 36106

South Asian (SAS) AF: 0.418 AC: 25945 AN: 62026

European-Finnish (FIN) AF: 0.180 AC: 9008 AN: 49926

Middle Eastern (MID) AF: 0.297 AC: 795 AN: 2680

European-Non Finnish (NFE) AF: 0.175 AC: 98669 AN: 563694

Other (OTH) AF: 0.257 AC: 9910 AN: 38512

GnomAD4 genome AF: 0.352 AC: 53609 AN: 152130 Hom.: 13100 Cov.: 33 AF XY: 0.353 AC XY: 26281 AN XY: 74392

African (AFR) AF: 0.689 AC: 28615 AN: 41506

American (AMR) AF: 0.323 AC: 4930 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 1041 AN: 3468

East Asian (EAS) AF: 0.287 AC: 1487 AN: 5178

South Asian (SAS) AF: 0.439 AC: 2118 AN: 4822

European-Finnish (FIN) AF: 0.181 AC: 1915 AN: 10596

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.184 AC: 12520 AN: 67970

Other (OTH) AF: 0.321 AC: 678 AN: 2110

Alfa AF: 0.252 Hom.: 13429

Bravo AF: 0.372

Asia WGS AF: 0.462 AC: 1605 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.34
DANN	Benign	0.60
PhyloP100		-0.77
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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

dbSNP: rs650877; hg19: chr1-207748793; COSMIC: COSV65457581; COSMIC: COSV65457581;