rs1057518643

Variant names:

• chr12-7088886-T-C
• rs1057518643
• NM_001733.7:c.869A>G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_001733.7(C1R):​c.869A>G​(p.Asp290Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: C1R NM_001733.7 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 7.07

Genes affected

C1R (HGNC:1246): (complement C1r) This gene encodes a member of the peptidase S1 protein family. The encoded protein is a proteolytic subunit in the complement system C1 complex. The complement system acts as a mediator in the innate immune response by ultimately triggering phagocytosis, inflammation, and rupturing the bacterial cell wall. Mutations in this gene are associated with Ehlers-Danlos Syndrome. [provided by RefSeq, Dec 2018]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a domain CUB 2 (size 112) in uniprot entity C1R_HUMAN there are 7 pathogenic changes around while only 3 benign (70%) in NM_001733.7
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 12-7088886-T-C is Pathogenic according to our data. Variant chr12-7088886-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 267356.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-7088886-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C1R	NM_001733.7	c.869A>G	p.Asp290Gly	missense_variant	Exon 6 of 11	ENST00000647956.2	NP_001724.4
C1R	NM_001354346.2	c.911A>G	p.Asp304Gly	missense_variant	Exon 6 of 11		NP_001341275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C1R	ENST00000647956.2	c.869A>G	p.Asp290Gly	missense_variant	Exon 6 of 11		NM_001733.7	ENSP00000497341.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Ehlers-Danlos syndrome, periodontal type 1 Pathogenic:2

Aug 23, 2016

Institute of Human Genetics, Medical University Innsbruck

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Oct 31, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Ehlers-Danlos syndrome, periodontal type 2 Pathogenic:1

Oct 13, 2016

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.040	.;.;T;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;.;D;D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Benign	-0.76	T
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-6.3	.;.;D;D
REVEL	Uncertain	0.61
Sift	Benign	0.042	.;.;D;D
Sift4G	Pathogenic	0.0	.;.;D;.
Polyphen		0.96, 0.44	.;.;D;B
Vest4		0.91, 0.91, 0.92
MutPred		0.93		Gain of catalytic residue at D290 (P = 0.1414);Gain of catalytic residue at D290 (P = 0.1414);.;.;
MVP		0.53
ClinPred		0.99	D
GERP RS		5.7
gMVP		0.95

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057518643; hg19: chr12-7241482;