1-207534292-A-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000651.6(CR1):c.1747A>C(p.Thr583Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.19 (56 hom., cov: 0)
  • Exomes 𝑓: 0.025 (47 hom.)
  • Failed GnomAD Quality Control
• Consequence: CR1 NM_000651.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.03

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0077373385).
• BP6: Variant 1-207534292-A-C is Benign according to our data. Variant chr1-207534292-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 2348399.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 8 BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CR1	NM_000651.6	c.1747A>C	p.Thr583Pro	missense_variant	11/47	ENST00000367049.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CR1	ENST00000367049.9	c.1747A>C	p.Thr583Pro	missense_variant	11/47	5	NM_000651.6	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1151 AN: 6128 Hom.: 56 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.260

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0750

Gnomad ASJ AF: 0.0172

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.125

Gnomad NFE AF: 0.00484

Gnomad OTH AF: 0.149

GnomAD3 exomes AF: 0.223 AC: 141 AN: 632 Hom.: 8 AF XY: 0.188 AC XY: 59 AN XY: 314

Gnomad AFR exome AF: 0.364

Gnomad AMR exome AF: 0.158

Gnomad ASJ exome AF: 0.167

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0114

Gnomad OTH exome AF: 0.125

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0252 AC: 718 AN: 28498 Hom.: 47 Cov.: 0 AF XY: 0.0227 AC XY: 339 AN XY: 14914

Gnomad4 AFR exome AF: 0.185

Gnomad4 AMR exome AF: 0.0437

Gnomad4 ASJ exome AF: 0.0108

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00504

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00143

Gnomad4 OTH exome AF: 0.0449

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.187 AC: 1152 AN: 6168 Hom.: 56 Cov.: 0 AF XY: 0.191 AC XY: 540 AN XY: 2830

Gnomad4 AFR AF: 0.258

Gnomad4 AMR AF: 0.0750

Gnomad4 ASJ AF: 0.0172

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00484

Gnomad4 OTH AF: 0.145

Alfa AF: 0.0152 Hom.: 14

ExAC AF: 0.0143 AC: 21

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	0.31
Dann	Benign	0.97
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0062	N
MetaRNN	Benign	0.0077	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.15	N;N;N;N
REVEL	Benign	0.088
Sift	Benign	0.18	T;T;T;T
Sift4G	Benign	0.16	T;T;T;T
Polyphen		0.45	.;.;.;P
Vest4		0.069
MPC		3.4
ClinPred		0.0072	T
GERP RS		-5.0
gMVP		0.049

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

Publications

LitVar

Other links and lift over

dbSNP: rs771009691; hg19: chr1-207707637;