rs1057518645

Positions:

• chr12-7086423-C-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1_Moderate PM1 PM2 PM5 PP5_Moderate

The NM_001733.7(C1R):​c.1073G>T​(p.Cys358Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C358Y) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: C1R NM_001733.7 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 6.05

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.

• PS1: Transcript NM_001733.7 (C1R) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a strand (size 3) in uniprot entity C1R_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001733.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-7086423-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2444516.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 12-7086423-C-A is Pathogenic according to our data. Variant chr12-7086423-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 267351.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-7086423-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C1R	NM_001733.7	c.1073G>T	p.Cys358Phe	missense_variant	8/11	ENST00000647956.2
C1R	NM_001354346.2	c.1115G>T	p.Cys372Phe	missense_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C1R	ENST00000647956.2	c.1073G>T	p.Cys358Phe	missense_variant	8/11		NM_001733.7	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 32

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
CADD	Uncertain	25
LIST_S2	Uncertain	0.89	D;.;D;D;D
MetaRNN	Uncertain	0.71	D;D;D;D;D
Vest4		0.80, 0.80, 0.79
gMVP		0.80

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057518645; hg19: -;