rs1057519580

Variant names:

• chr12-7085919-GTAGTACTGGATACGG-TATTACATGA
• rs1057519580
• NM_001733.7:c.1200_1215delCCGTATCCAGTACTACinsTCATGTAATA

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM4 PP5_Moderate

The NM_001733.7(C1R):​c.1200_1215delCCGTATCCAGTACTACinsTCATGTAATA​(p.Arg401_Tyr405delinsHisValIle) variant causes a missense, conservative inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: C1R NM_001733.7 missense, conservative_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.91
• Publications: 1 publications found

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]

C1R Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome, periodontal type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal systemic lupus erythematosus type 16

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ehlers-Danlos syndrome, periodontitis type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001733.7.
• PP5: Variant 12-7085919-GTAGTACTGGATACGG-TATTACATGA is Pathogenic according to our data. Variant chr12-7085919-GTAGTACTGGATACGG-TATTACATGA is described in ClinVar as Pathogenic. ClinVar VariationId is 375581.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001733.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1R	NM_001733.7	MANE Select	c.1200_1215delCCGTATCCAGTACTACinsTCATGTAATA	p.Arg401_Tyr405delinsHisValIle	missense conservative_inframe_deletion	N/A	NP_001724.4
	C1R	NM_001354346.2		c.1242_1257delCCGTATCCAGTACTACinsTCATGTAATA	p.Arg415_Tyr419delinsHisValIle	missense conservative_inframe_deletion	N/A	NP_001341275.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1R	ENST00000647956.2	MANE Select	c.1200_1215delCCGTATCCAGTACTACinsTCATGTAATA	p.Arg401_Tyr405delinsHisValIle	missense conservative_inframe_deletion	N/A	ENSP00000497341.1
	C1R	ENST00000536053.6	TSL:2	c.1242_1257delCCGTATCCAGTACTACinsTCATGTAATA	p.Arg415_Tyr419delinsHisValIle	missense conservative_inframe_deletion	N/A	ENSP00000444271.3
	C1R	ENST00000535233.6	TSL:2	c.1098_1113delCCGTATCCAGTACTACinsTCATGTAATA	p.Arg367_Tyr371delinsHisValIle	missense conservative_inframe_deletion	N/A	ENSP00000438636.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Ehlers-Danlos syndrome, periodontal type 1 (1)
1	-	-	Ehlers-Danlos syndrome, periodontal type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.9

Splicing

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

Other links and lift over

dbSNP: rs1057519580;