12-7090357-A-G

Position:

• chr12-7090357-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001733.7(C1R):​c.232-109T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 625,160 control chromosomes in the GnomAD database, including 20,851 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4000 hom., cov: 32)
  • Exomes 𝑓: 0.25 (16851 hom.)
• Consequence: C1R NM_001733.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.09

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]

C1RL (HGNC:21265): (complement C1r subcomponent like) Predicted to enable serine-type endopeptidase activity. Predicted to be involved in zymogen activation. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 12-7090357-A-G is Benign according to our data. Variant chr12-7090357-A-G is described in ClinVar as [Benign]. Clinvar id is 1283181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.46 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C1R	NM_001733.7	c.232-109T>C		intron_variant		ENST00000647956.2
C1R	NM_001354346.2	c.274-109T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C1R	ENST00000647956.2	c.232-109T>C		intron_variant			NM_001733.7	P1

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32282 AN: 152016 Hom.: 3995 Cov.: 32

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.404

Gnomad FIN AF: 0.186

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.213

Gnomad OTH AF: 0.229

GnomAD4 exome AF: 0.251 AC: 118765 AN: 473026 Hom.: 16851 Cov.: 0 AF XY: 0.258 AC XY: 64572 AN XY: 250338

Gnomad4 AFR exome AF: 0.128

Gnomad4 AMR exome AF: 0.390

Gnomad4 ASJ exome AF: 0.173

Gnomad4 EAS exome AF: 0.455

Gnomad4 SAS exome AF: 0.383

Gnomad4 FIN exome AF: 0.194

Gnomad4 NFE exome AF: 0.212

Gnomad4 OTH exome AF: 0.238

GnomAD4 genome AF: 0.212 AC: 32315 AN: 152134 Hom.: 4000 Cov.: 32 AF XY: 0.218 AC XY: 16225 AN XY: 74370

Gnomad4 AFR AF: 0.128

Gnomad4 AMR AF: 0.319

Gnomad4 ASJ AF: 0.166

Gnomad4 EAS AF: 0.476

Gnomad4 SAS AF: 0.404

Gnomad4 FIN AF: 0.186

Gnomad4 NFE AF: 0.213

Gnomad4 OTH AF: 0.230

Alfa AF: 0.202 Hom.: 664

Bravo AF: 0.217

Asia WGS AF: 0.405 AC: 1408 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.15
DANN	Benign	0.24

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4505141; hg19: chr12-7242953;