rs3737002

Variant names:

• chr1-207587428-C-T
• rs3737002
• NM_000651.6:c.5573C>T

Variant summary

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

The NM_000651.6(CR1):​c.5573C>T​(p.Thr1858Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 1,613,346 control chromosomes in the GnomAD database, including 64,072 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1858A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.23 (4928 hom., cov: 33)
  • Exomes 𝑓: 0.28 (59144 hom.)
• Consequence: CR1 NM_000651.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.587
• Publications: 59 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 (MetaRNN=0.00201419).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000651.6. 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
	CR1	NM_000651.6	MANE Select	c.5573C>T	p.Thr1858Met	missense	Exon 34 of 47	NP_000642.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CR1	ENST00000367049.9	TSL:5 MANE Select	c.5573C>T	p.Thr1858Met	missense	Exon 34 of 47	ENSP00000356016.4
	CR1	ENST00000400960.7	TSL:1	c.4223C>T	p.Thr1408Met	missense	Exon 26 of 39	ENSP00000383744.2
	CR1	ENST00000367051.6	TSL:5	c.4223C>T	p.Thr1408Met	missense	Exon 26 of 39	ENSP00000356018.1

Frequencies

GnomAD3 genomes AF: 0.230 AC: 34978 AN: 152024 Hom.: 4922 Cov.: 33

Gnomad AFR AF: 0.0754

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.245

Gnomad EAS AF: 0.329

Gnomad SAS AF: 0.305

Gnomad FIN AF: 0.324

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.275

Gnomad OTH AF: 0.241

GnomAD2 exomes AF: 0.282 AC: 70327 AN: 248984 AF XY: 0.283

Gnomad AFR exome AF: 0.0709

Gnomad AMR exome AF: 0.359

Gnomad ASJ exome AF: 0.239

Gnomad EAS exome AF: 0.330

Gnomad FIN exome AF: 0.327

Gnomad NFE exome AF: 0.268

Gnomad OTH exome AF: 0.276

GnomAD4 exome AF: 0.280 AC: 409370 AN: 1461204 Hom.: 59144 Cov.: 34 AF XY: 0.281 AC XY: 204001 AN XY: 726916

African (AFR) AF: 0.0672 AC: 2250 AN: 33466

American (AMR) AF: 0.354 AC: 15816 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 6171 AN: 26130

East Asian (EAS) AF: 0.348 AC: 13799 AN: 39688

South Asian (SAS) AF: 0.307 AC: 26511 AN: 86240

European-Finnish (FIN) AF: 0.321 AC: 17142 AN: 53396

Middle Eastern (MID) AF: 0.216 AC: 1247 AN: 5768

European-Non Finnish (NFE) AF: 0.279 AC: 310576 AN: 1111442

Other (OTH) AF: 0.263 AC: 15858 AN: 60358

GnomAD4 genome AF: 0.230 AC: 34990 AN: 152142 Hom.: 4928 Cov.: 33 AF XY: 0.237 AC XY: 17614 AN XY: 74370

African (AFR) AF: 0.0754 AC: 3131 AN: 41530

American (AMR) AF: 0.316 AC: 4837 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 848 AN: 3468

East Asian (EAS) AF: 0.330 AC: 1705 AN: 5174

South Asian (SAS) AF: 0.306 AC: 1473 AN: 4812

European-Finnish (FIN) AF: 0.324 AC: 3425 AN: 10568

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.275 AC: 18671 AN: 67992

Other (OTH) AF: 0.239 AC: 504 AN: 2112

Alfa AF: 0.255 Hom.: 13003

Bravo AF: 0.224

TwinsUK AF: 0.293 AC: 1087

ALSPAC AF: 0.281 AC: 1082

ESP6500AA AF: 0.0748 AC: 272

ESP6500EA AF: 0.276 AC: 2253

ExAC AF: 0.275 AC: 33182

Asia WGS AF: 0.262 AC: 912 AN: 3478

EpiCase AF: 0.267

EpiControl AF: 0.265

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	4.2
DANN	Uncertain	0.99
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.0090	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.59
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.092
Sift	Uncertain	0.019	D
Sift4G	Benign	0.11	T
Polyphen		0.99	D
Vest4		0.13
MPC		0.52
ClinPred		0.012	T
GERP RS		-0.082
gMVP		0.46
Mutation Taster		=100/0	polymorphism (auto)

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

dbSNP: rs3737002; hg19: chr1-207760773; COSMIC: COSV65458238;