12-7080480-GTT-GTTTTT

Variant names:

• chr12-7080480-G-GTTT
• rs374614759
• NM_001733.7:c.*49_*51dupAAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001733.7(C1R):​c.*49_*51dupAAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000371 in 1,077,630 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000037 (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: Genomics England PanelApp, G2P, 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.*49_*51dupAAA		3_prime_UTR	Exon 11 of 11	NP_001724.4	A0A3B3ISR2
	C1R	NM_001354346.2		c.*49_*51dupAAA		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.*49_*51dupAAA		3_prime_UTR	Exon 11 of 11	ENSP00000497341.1	A0A3B3ISR2
	C1R	ENST00000649804.1		c.*49_*51dupAAA		splice_region	Exon 5 of 5	ENSP00000497938.1	A0A3B3ITU4
	C1R	ENST00000903851.1		c.*49_*51dupAAA		3_prime_UTR	Exon 12 of 12	ENSP00000573910.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000371 AC: 4 AN: 1077630 Hom.: 0 Cov.: 32 AF XY: 0.00000569 AC XY: 3 AN XY: 526842

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

African (AFR) AF: 0.0000422 AC: 1 AN: 23672

American (AMR) AF: 0.00 AC: 0 AN: 22138

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15924

East Asian (EAS) AF: 0.00 AC: 0 AN: 29376

South Asian (SAS) AF: 0.00 AC: 0 AN: 55088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4564

European-Non Finnish (NFE) AF: 0.00000355 AC: 3 AN: 844314

Other (OTH) AF: 0.00 AC: 0 AN: 43958

⚠️ 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;