chr1-207563903-C-A

Variant names:

• chr1-207563903-C-A
• rs776512609
• NM_000651.6:c.3626C>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000651.6(CR1):​c.3626C>A​(p.Thr1209Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 15)
  • Exomes 𝑓: 0.0000079 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: CR1 NM_000651.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.597
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.049437076).

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.3626C>A	p.Thr1209Asn	missense	Exon 22 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.3626C>A	p.Thr1209Asn	missense	Exon 22 of 47	ENSP00000356016.4	E9PDY4
	CR1	ENST00000400960.7	TSL:1	c.2276C>A	p.Thr759Asn	missense	Exon 14 of 39	ENSP00000383744.2	P17927
	CR1	ENST00000367051.6	TSL:5	c.2276C>A	p.Thr759Asn	missense	Exon 14 of 39	ENSP00000356018.1	P17927

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 105510 Hom.: 0 Cov.: 15

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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: 0.0000545 AC: 12 AN: 220118 AF XY: 0.0000333

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000398

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000794 AC: 11 AN: 1386248 Hom.: 1 Cov.: 31 AF XY: 0.00000290 AC XY: 2 AN XY: 690212

African (AFR) AF: 0.00 AC: 0 AN: 17224

American (AMR) AF: 0.000270 AC: 11 AN: 40694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24432

East Asian (EAS) AF: 0.00 AC: 0 AN: 38234

South Asian (SAS) AF: 0.00 AC: 0 AN: 76928

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1075844

Other (OTH) AF: 0.00 AC: 0 AN: 56562

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 105510 Hom.: 0 Cov.: 15 AF XY: 0.00 AC XY: 0 AN XY: 50742

African (AFR) AF: 0.00 AC: 0 AN: 12470

American (AMR) AF: 0.00 AC: 0 AN: 10962

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2936

East Asian (EAS) AF: 0.00 AC: 0 AN: 4198

South Asian (SAS) AF: 0.00 AC: 0 AN: 2902

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 60842

Other (OTH) AF: 0.00 AC: 0 AN: 1520

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000751 AC: 8

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	0.12
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	1.1
DANN	Benign	0.88
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0050	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-0.93	T
PhyloP100		-0.60
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.031
Sift	Benign	0.36	T
Sift4G	Benign	0.10	T
Polyphen		0.060	B
Vest4		0.093
MutPred		0.34		Loss of phosphorylation at T1209 (P = 0.0054)
MVP		0.48
MPC		2.5
ClinPred		0.051	T
GERP RS		-2.2
gMVP		0.15
Mutation Taster		=100/0	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

dbSNP: rs776512609; hg19: chr1-207737248;