12-7090085-T-A

Position:

• chr12-7090085-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001733.7(C1R):​c.395A>T​(p.Lys132Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000016 in 625,134 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: C1R NM_001733.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.412

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C1R	NM_001733.7	c.395A>T	p.Lys132Met	missense_variant	3/11	ENST00000647956.2	NP_001724.4
C1R	NM_001354346.2	c.437A>T	p.Lys146Met	missense_variant	3/11		NP_001341275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C1R	ENST00000647956.2	c.395A>T	p.Lys132Met	missense_variant	3/11		NM_001733.7	ENSP00000497341	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000160 AC: 1 AN: 625134 Hom.: 0 Cov.: 0 AF XY: 0.00000294 AC XY: 1 AN XY: 340272

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000231

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 03, 2023

Variant summary: C1R c.395A>T (p.Lys132Met) results in a non-conservative amino acid change located in the CUB domain (IPR000859) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 243426 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.395A>T in individuals affected with Ehlers-Danlos Syndrome, Periodontal Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	.;.;T;T;T;.;T;.;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.89	D;.;D;D;D;D;D;D;D
MetaRNN	Uncertain	0.54	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.71	T
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.4	.;.;N;N;D;N;D;D;D
REVEL	Benign	0.24
Sift	Uncertain	0.0060	.;.;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	.;.;D;.;.;.;.;.;D
Polyphen		1.0	.;.;D;D;.;.;.;.;.
Vest4		0.58, 0.59, 0.63
MutPred		0.61		Loss of methylation at K132 (P = 0.0042);Loss of methylation at K132 (P = 0.0042);.;.;.;.;.;Loss of methylation at K132 (P = 0.0042);.;
MVP		0.34
ClinPred		0.99	D
GERP RS		5.4
gMVP		0.52

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs780249848; hg19: chr12-7242681;