NM_001733.7:c.336G>T

Variant names:

• chr12-7090144-C-A
• NM_001733.7:c.336G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001733.7(C1R):​c.336G>T​(p.Met112Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000161 in 622,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: C1R NM_001733.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.89

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.802

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C1R	NM_001733.7	c.336G>T	p.Met112Ile	missense_variant	Exon 3 of 11	ENST00000647956.2	NP_001724.4
C1R	NM_001354346.2	c.378G>T	p.Met126Ile	missense_variant	Exon 3 of 11		NP_001341275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C1R	ENST00000647956.2	c.336G>T	p.Met112Ile	missense_variant	Exon 3 of 11		NM_001733.7	ENSP00000497341.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000161 AC: 1 AN: 622830 Hom.: 0 Cov.: 0 AF XY: 0.00000295 AC XY: 1 AN XY: 338904

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000288

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	.;.;T;T;T;.;T;.;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.88	D;.;D;T;D;T;D;D;D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.57	T
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.8	.;.;D;N;D;D;D;N;D
REVEL	Uncertain	0.34
Sift	Benign	0.040	.;.;D;D;D;D;D;D;D
Sift4G	Uncertain	0.050	.;.;T;.;.;.;.;.;D
Polyphen		0.99, 1.0	.;.;D;D;.;.;.;.;.
Vest4		0.84, 0.84, 0.81
MutPred		0.69		Gain of methylation at K111 (P = 0.0334);Gain of methylation at K111 (P = 0.0334);.;.;.;.;.;Gain of methylation at K111 (P = 0.0334);.;
MVP		0.21
ClinPred		1.0	D
GERP RS		5.4
gMVP		0.41

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-7242740;