1-207564171-G-A

Variant names:

• chr1-207564171-G-A
• rs777009868
• NM_000651.6:c.3803G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000651.6(CR1):​c.3803G>A​(p.Gly1268Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000315 in 1,585,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 24)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CR1 NM_000651.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.09
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.913

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.3803G>A	p.Gly1268Asp	missense	Exon 23 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.3803G>A	p.Gly1268Asp	missense	Exon 23 of 47	ENSP00000356016.4	E9PDY4
	CR1	ENST00000400960.7	TSL:1	c.2453G>A	p.Gly818Asp	missense	Exon 15 of 39	ENSP00000383744.2	P17927
	CR1	ENST00000367051.6	TSL:5	c.2453G>A	p.Gly818Asp	missense	Exon 15 of 39	ENSP00000356018.1	P17927

Frequencies

GnomAD3 genomes AF: 0.0000143 AC: 2 AN: 139930 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000403

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000164 AC: 4 AN: 243972 AF XY: 0.0000151

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000225

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1445660 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 719352

African (AFR) AF: 0.00 AC: 0 AN: 28854

American (AMR) AF: 0.00 AC: 0 AN: 44414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25998

East Asian (EAS) AF: 0.0000758 AC: 3 AN: 39598

South Asian (SAS) AF: 0.00 AC: 0 AN: 85596

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4196

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104122

Other (OTH) AF: 0.00 AC: 0 AN: 59584

GnomAD4 genome AF: 0.0000143 AC: 2 AN: 139930 Hom.: 0 Cov.: 24 AF XY: 0.0000147 AC XY: 1 AN XY: 67960

African (AFR) AF: 0.00 AC: 0 AN: 32260

American (AMR) AF: 0.00 AC: 0 AN: 14412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3432

East Asian (EAS) AF: 0.000403 AC: 2 AN: 4960

South Asian (SAS) AF: 0.00 AC: 0 AN: 4370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67070

Other (OTH) AF: 0.00 AC: 0 AN: 1920

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000333 AC: 4

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	Pathogenic	0.91
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.013
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.013	T
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-0.88	T
PhyloP100		4.1
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.30
Sift	Benign	0.061	T
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.84		Loss of stability (P = 0.2397)
MVP		0.65
MPC		3.9
ClinPred		0.58	D
GERP RS		2.0
gMVP		0.75
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs777009868; hg19: chr1-207737516;