rs1060499554

Positions:

• chr12-7082077-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001733.7(C1R):​c.1303T>C​(p.Trp435Arg) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: C1R NM_001733.7 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.58

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959
• PP5: Variant 12-7082077-A-G is Pathogenic according to our data. Variant chr12-7082077-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 375582.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C1R	NM_001733.7	c.1303T>C	p.Trp435Arg	missense_variant	10/11	ENST00000647956.2	NP_001724.4
C1R	NM_001354346.2	c.1345T>C	p.Trp449Arg	missense_variant	10/11		NP_001341275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C1R	ENST00000647956.2	c.1303T>C	p.Trp435Arg	missense_variant	10/11		NM_001733.7	ENSP00000497341	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

- -

Ehlers-Danlos syndrome, periodontal type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Institute of Human Genetics, Medical University Innsbruck

Aug 23, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	.;.;T;T;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.56	T;.;T;T;T
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Uncertain	0.78	D
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.67	T
REVEL	Pathogenic	0.71
Sift4G	Pathogenic	0.0	.;.;D;.;.
Vest4		0.74, 0.70, 0.69
MutPred		0.83		Gain of disorder (P = 5e-04);Gain of disorder (P = 5e-04);.;.;.;
MVP		0.86
ClinPred		0.97	D
GERP RS		4.3
gMVP		0.91

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060499554; hg19: chr12-7189381;