12-7080480-GTT-GTTT

Variant names:

• chr12-7080480-G-GT
• rs374614759
• NM_001733.7:c.*51dupA

Variant summary

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

The NM_001733.7(C1R):​c.*51dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0716 in 919,626 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), 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: 𝑓 0.00050 (0 hom., cov: 31)
  • Exomes 𝑓: 0.085 (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.*51dupA		3_prime_UTR	Exon 11 of 11	NP_001724.4	A0A3B3ISR2
	C1R	NM_001354346.2		c.*51dupA		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.*51dupA		3_prime_UTR	Exon 11 of 11	ENSP00000497341.1	A0A3B3ISR2
	C1R	ENST00000649804.1		c.*51dupA		splice_region	Exon 5 of 5	ENSP00000497938.1	A0A3B3ITU4
	C1R	ENST00000903851.1		c.*51dupA		3_prime_UTR	Exon 12 of 12	ENSP00000573910.1

Frequencies

GnomAD3 genomes AF: 0.000498 AC: 73 AN: 146552 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000349

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000478

Gnomad ASJ AF: 0.000588

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000216

Gnomad FIN AF: 0.00247

Gnomad MID AF: 0.00649

Gnomad NFE AF: 0.000317

Gnomad OTH AF: 0.00150

GnomAD4 exome AF: 0.0851 AC: 65749 AN: 772994 Hom.: 0 Cov.: 32 AF XY: 0.0853 AC XY: 32375 AN XY: 379690

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

African (AFR) AF: 0.0885 AC: 1486 AN: 16782

American (AMR) AF: 0.111 AC: 1832 AN: 16520

Ashkenazi Jewish (ASJ) AF: 0.0773 AC: 934 AN: 12078

East Asian (EAS) AF: 0.0975 AC: 1913 AN: 19622

South Asian (SAS) AF: 0.108 AC: 4887 AN: 45376

European-Finnish (FIN) AF: 0.0755 AC: 2310 AN: 30576

Middle Eastern (MID) AF: 0.0491 AC: 187 AN: 3808

European-Non Finnish (NFE) AF: 0.0829 AC: 49454 AN: 596422

Other (OTH) AF: 0.0863 AC: 2746 AN: 31810

⚠️ 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 AF: 0.000498 AC: 73 AN: 146632 Hom.: 0 Cov.: 31 AF XY: 0.000491 AC XY: 35 AN XY: 71306

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

African (AFR) AF: 0.000348 AC: 14 AN: 40192

American (AMR) AF: 0.000478 AC: 7 AN: 14656

Ashkenazi Jewish (ASJ) AF: 0.000588 AC: 2 AN: 3404

East Asian (EAS) AF: 0.00 AC: 0 AN: 5044

South Asian (SAS) AF: 0.000217 AC: 1 AN: 4618

European-Finnish (FIN) AF: 0.00247 AC: 23 AN: 9324

Middle Eastern (MID) AF: 0.00704 AC: 2 AN: 284

European-Non Finnish (NFE) AF: 0.000317 AC: 21 AN: 66192

Other (OTH) AF: 0.00149 AC: 3 AN: 2020

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000000000000777156), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 12

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; COSMIC: COSV73382906;