12-7089732-G-A

Variant names:

• chr12-7089732-G-A
• rs147288661
• NM_001733.7:c.426C>T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_001733.7(C1R):​c.426C>T​(p.Asp142Asp) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000247 in 780,678 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00072 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: C1R NM_001733.7 splice_region, synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.26

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 12-7089732-G-A is Benign according to our data. Variant chr12-7089732-G-A is described in ClinVar as [Benign]. Clinvar id is 3768294.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.26 with no splicing effect.
• BS2: High AC in GnomAd4 at 110 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C1R	NM_001733.7	c.426C>T	p.Asp142Asp	splice_region_variant, synonymous_variant	Exon 4 of 11	ENST00000647956.2	NP_001724.4
C1R	NM_001354346.2	c.468C>T	p.Asp156Asp	splice_region_variant, synonymous_variant	Exon 4 of 11		NP_001341275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C1R	ENST00000647956.2	c.426C>T	p.Asp142Asp	splice_region_variant, synonymous_variant	Exon 4 of 11		NM_001733.7	ENSP00000497341.1

Frequencies

GnomAD3 genomes AF: 0.000703 AC: 107 AN: 152222 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000217 AC: 54 AN: 248628 Hom.: 0 AF XY: 0.000178 AC XY: 24 AN XY: 134870

Gnomad AFR exome AF: 0.00253

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000443

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000132 AC: 83 AN: 628338 Hom.: 0 Cov.: 0 AF XY: 0.000120 AC XY: 41 AN XY: 342276

Gnomad4 AFR exome AF: 0.00260

Gnomad4 AMR exome AF: 0.000297

Gnomad4 ASJ exome AF: 0.0000477

Gnomad4 EAS exome AF: 0.0000277

Gnomad4 SAS exome AF: 0.0000287

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000343

Gnomad4 OTH exome AF: 0.000181

GnomAD4 genome AF: 0.000722 AC: 110 AN: 152340 Hom.: 1 Cov.: 32 AF XY: 0.000805 AC XY: 60 AN XY: 74498

Gnomad4 AFR AF: 0.00253

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000144 Hom.: 0

Bravo AF: 0.000861

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Dec 03, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	10
DANN	Benign	0.76

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs147288661; hg19: chr12-7242328;