chr1-207496337-G-A

Variant names:

• chr1-207496337-G-A
• rs1659080537
• NM_000651.6:c.70G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000651.6(CR1):​c.70G>A​(p.Gly24Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CR1 NM_000651.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.08

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08381751).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CR1	NM_000651.6	c.70G>A	p.Gly24Arg	missense_variant	Exon 1 of 47	ENST00000367049.9	NP_000642.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CR1	ENST00000367049.9	c.70G>A	p.Gly24Arg	missense_variant	Exon 1 of 47	5	NM_000651.6	ENSP00000356016.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460890 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726670

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.70G>A (p.G24R) alteration is located in exon 1 (coding exon 1) of the CR1 gene. This alteration results from a G to A substitution at nucleotide position 70, causing the glycine (G) at amino acid position 24 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	1.7
DANN	Uncertain	0.99
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.50	.;.;.;T;T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.084	T;T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.90	N;N;N;N;N
REVEL	Benign	0.046
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Uncertain	0.032	D;D;D;D;D
Polyphen		0.42	.;.;.;B;B
Vest4		0.22
MutPred		0.47		Loss of catalytic residue at P20 (P = 0.0722);Loss of catalytic residue at P20 (P = 0.0722);Loss of catalytic residue at P20 (P = 0.0722);Loss of catalytic residue at P20 (P = 0.0722);Loss of catalytic residue at P20 (P = 0.0722);
MVP		0.38
MPC		0.079
ClinPred		0.13	T
GERP RS		0.62
gMVP		0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs1659080537; hg19: chr1-207669682;