chr12-7080480-G-GTT

Variant names:

• chr12-7080480-G-GTT
• rs374614759
• NM_001733.7:c.*50_*51dupAA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001733.7(C1R):​c.*50_*51dupAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000782 in 1,074,742 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000078 (0 hom.)
• Consequence: C1R NM_001733.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00
• Publications: 0 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: G2P, PanelApp Australia, 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: Uncertain_significance. The variant received 0 ACMG points.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1R	NM_001733.7	MANE Select	c.*50_*51dupAA		3_prime_UTR	Exon 11 of 11	NP_001724.4	A0A3B3ISR2
	C1R	NM_001354346.2		c.*50_*51dupAA		3_prime_UTR	Exon 11 of 11	NP_001341275.1	B4DPQ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1R	ENST00000647956.2	MANE Select	c.*50_*51dupAA		3_prime_UTR	Exon 11 of 11	ENSP00000497341.1	A0A3B3ISR2
	C1R	ENST00000649804.1		c.*50_*51dupAA		splice_region	Exon 5 of 5	ENSP00000497938.1	A0A3B3ITU4
	C1R	ENST00000903851.1		c.*50_*51dupAA		3_prime_UTR	Exon 12 of 12	ENSP00000573910.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000782 AC: 84 AN: 1074742 Hom.: 0 Cov.: 32 AF XY: 0.0000914 AC XY: 48 AN XY: 525370

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000847 AC: 2 AN: 23608

American (AMR) AF: 0.000227 AC: 5 AN: 22040

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15886

East Asian (EAS) AF: 0.0000342 AC: 1 AN: 29278

South Asian (SAS) AF: 0.000310 AC: 17 AN: 54802

European-Finnish (FIN) AF: 0.000130 AC: 5 AN: 38496

Middle Eastern (MID) AF: 0.000220 AC: 1 AN: 4550

European-Non Finnish (NFE) AF: 0.0000594 AC: 50 AN: 842252

Other (OTH) AF: 0.0000684 AC: 3 AN: 43830

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0

Splicing

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

Other links and lift over

dbSNP: rs374614759; hg19: chr12-7187784;