rs1057519026

Positions:

• chr12-7088865-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_001733.7(C1R):​c.890G>A​(p.Gly297Asp) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: C1R NM_001733.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.97

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 16 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001733.7
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 12-7088865-C-T is Pathogenic according to our data. Variant chr12-7088865-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C1R	NM_001733.7	c.890G>A	p.Gly297Asp	missense_variant	6/11	ENST00000647956.2
C1R	NM_001354346.2	c.932G>A	p.Gly311Asp	missense_variant	6/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C1R	ENST00000647956.2	c.890G>A	p.Gly297Asp	missense_variant	6/11		NM_001733.7	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ehlers-Danlos syndrome, periodontal type 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Dec 12, 2023	- -
Pathogenic, criteria provided, single submitter	research	Institute of Human Genetics, Medical University Innsbruck	Aug 23, 2016	- -

Ehlers-Danlos syndrome, periodontal type 2 Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

Oct 13, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	.;.;T;T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;.;D;D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Benign	-0.54	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.5	.;.;D;D
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	.;.;D;D
Sift4G	Pathogenic	0.0	.;.;D;.
Polyphen		1.0	.;.;D;D
Vest4		0.95, 0.95
MutPred		0.94		Gain of ubiquitination at K299 (P = 0.0526);Gain of ubiquitination at K299 (P = 0.0526);.;.;
MVP		0.68
ClinPred		1.0	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: rs1057519026; hg19: chr12-7241461;