1-207552816-G-T

Variant names:

• chr1-207552816-G-T
• rs3738467
• NM_000651.6:c.3066G>T

Variant summary

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

The NM_000651.6(CR1):​c.3066G>T​(p.Gln1022His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.14 (14 hom., cov: 11)
  • Exomes 𝑓: 0.19 (405 hom.)
  • Failed GnomAD Quality Control
• Consequence: CR1 NM_000651.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.459
• Publications: 13 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=0.0076934695).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CR1	NM_000651.6	c.3066G>T	p.Gln1022His	missense_variant	Exon 19 of 47	ENST00000367049.9	NP_000642.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CR1	ENST00000367049.9	c.3066G>T	p.Gln1022His	missense_variant	Exon 19 of 47	5	NM_000651.6	ENSP00000356016.4

Frequencies

GnomAD3 genomes AF: 0.143 AC: 11972 AN: 83716 Hom.: 14 Cov.: 11

Gnomad AFR AF: 0.0966

Gnomad AMI AF: 0.219

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.298

Gnomad SAS AF: 0.334

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.147

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.153

GnomAD2 exomes AF: 0.00137 AC: 4 AN: 2912 AF XY: 0.000687

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00149

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0119

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00144

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.186 AC: 168093 AN: 905110 Hom.: 405 Cov.: 12 AF XY: 0.191 AC XY: 88393 AN XY: 462120

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.103 AC: 2539 AN: 24538

American (AMR) AF: 0.252 AC: 8576 AN: 34060

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 5148 AN: 20212

East Asian (EAS) AF: 0.272 AC: 6573 AN: 24138

South Asian (SAS) AF: 0.329 AC: 23309 AN: 70764

European-Finnish (FIN) AF: 0.142 AC: 6517 AN: 45810

Middle Eastern (MID) AF: 0.239 AC: 773 AN: 3232

European-Non Finnish (NFE) AF: 0.166 AC: 106847 AN: 641900

Other (OTH) AF: 0.193 AC: 7811 AN: 40456

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.143 AC: 11990 AN: 83844 Hom.: 14 Cov.: 11 AF XY: 0.148 AC XY: 5928 AN XY: 40150

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0963 AC: 2306 AN: 23958

American (AMR) AF: 0.198 AC: 1606 AN: 8126

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 517 AN: 2146

East Asian (EAS) AF: 0.296 AC: 399 AN: 1346

South Asian (SAS) AF: 0.334 AC: 589 AN: 1762

European-Finnish (FIN) AF: 0.131 AC: 673 AN: 5146

Middle Eastern (MID) AF: 0.143 AC: 22 AN: 154

European-Non Finnish (NFE) AF: 0.141 AC: 5595 AN: 39656

Other (OTH) AF: 0.160 AC: 151 AN: 946

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0553 Hom.: 3

ExAC AF: 0.00143 AC: 6

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	6.0
DANN	Uncertain	0.99
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.37	.;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0077	T;T;T
MetaSVM	Benign	-0.84	T
PhyloP100		-0.46
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.16
Sift	Uncertain	0.029	D;T;D
Sift4G	Benign	0.18	T;D;D
Polyphen		0.99	.;.;D
Vest4		0.13
MutPred		0.51		.;Gain of phosphorylation at T1019 (P = 0.238);Gain of phosphorylation at T1019 (P = 0.238);
MVP		0.66
MPC		2.0
ClinPred		0.027	T
GERP RS		-0.16
gMVP		0.050
Mutation Taster		=96/4	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: rs3738467; hg19: chr1-207726161; COSMIC: COSV65455602;