1-207563917-G-T

Position:

• chr1-207563917-G-T

Variant summary

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

The NM_000651.6(CR1):​c.3640G>T​(p.Asp1214Tyr) 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. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 16)
• Consequence: CR1 NM_000651.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.536

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]

(HGNC:):

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=0.16796869).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CR1	NM_000651.6	c.3640G>T	p.Asp1214Tyr	missense_variant	22/47	ENST00000367049.9	NP_000642.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CR1	ENST00000367049.9	c.3640G>T	p.Asp1214Tyr	missense_variant	22/47	5	NM_000651.6	ENSP00000356016	P1
	ENST00000597497.5	n.353-10937C>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 16

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 16

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2022

The c.2290G>T (p.D764Y) alteration is located in exon 14 (coding exon 14) of the CR1 gene. This alteration results from a G to T substitution at nucleotide position 2290, causing the aspartic acid (D) at amino acid position 764 to be replaced by a tyrosine (Y). 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	0.25
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	14
DANN	Benign	0.97
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.77	.;.;.;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Benign	-0.66	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.30	T;T;T;D
Sift4G	Benign	0.099	T;T;T;D
Polyphen		0.99	.;.;.;D
Vest4		0.16
MutPred		0.46		.;.;.;Gain of phosphorylation at D1214 (P = 0.0292);
MVP		0.75
MPC		3.5
ClinPred		0.34	T
GERP RS		1.1
gMVP		0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-207737262;