rs1057515579

chr12-7088856-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PP3_Strong PP5_Moderate

The NM_001733.7(C1R):c.899T>C(p.Leu300Pro) variant causes a missense change involving the alteration of a conserved nucleotide. 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: 8.24

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 Likely_pathogenic. Variant got 8 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 12-7088856-A-G is Pathogenic according to our data. Variant chr12-7088856-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 267354.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C1R	NM_001733.7	c.899T>C	p.Leu300Pro	missense_variant	6/11	ENST00000647956.2
C1R	NM_001354346.2	c.941T>C	p.Leu314Pro	missense_variant	6/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C1R	ENST00000647956.2	c.899T>C	p.Leu300Pro	missense_variant	6/11		NM_001733.7	P1

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

Pathogenic, criteria provided, single submitter	research	Institute of Human Genetics, Medical University Innsbruck	Aug 23, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 31, 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	0.30	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;.;T;T
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Benign	-0.77	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.51	T
Polyphen		1.0, 1.0	.;.;D;D
Vest4		0.85, 0.87, 0.86
MutPred		0.85		Gain of disorder (P = 0.0299);Gain of disorder (P = 0.0299);.;.;
MVP		0.42
ClinPred		0.99	D
GERP RS		5.7
gMVP		0.93

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057515579; hg19: chr12-7241452;