rs1057519576

Positions:

• chr12-7088850-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_Moderate PM1 PM2 PP3_Strong PP5_Moderate

The NM_001733.7(C1R):​c.905A>G​(p.Tyr302Cys) 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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Genomes: not found (cov: 31)
• Consequence: C1R NM_001733.7 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• 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 12 ACMG points.

• PS1: Transcript NM_001733.7 (C1R) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_001733.7
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 12-7088850-T-C is Pathogenic according to our data. Variant chr12-7088850-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 375577.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.905A>G	p.Tyr302Cys	missense_variant	6/11	ENST00000647956.2
C1R	NM_001354346.2	c.947A>G	p.Tyr316Cys	missense_variant	6/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C1R	ENST00000647956.2	c.905A>G	p.Tyr302Cys	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: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	0.92
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	.;.;T;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;.;D;D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Benign	-0.57	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-8.2	.;.;D;D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	.;.;D;D
Sift4G	Pathogenic	0.0	.;.;D;.
Polyphen		1.0	.;.;D;D
Vest4		0.93, 0.93, 0.93
MutPred		0.89		Gain of methylation at K299 (P = 0.1143);Gain of methylation at K299 (P = 0.1143);.;.;
MVP		0.60
ClinPred		1.0	D
GERP RS		5.7
gMVP		0.96

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057519576; hg19: chr12-7241446;