rs1057519576

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_ModeratePM1PM2PP3_StrongPP5_Moderate

The NM_001733.7(C1R):​c.905A>G​(p.Tyr302Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: not found (cov: 31)

Consequence

C1R
NM_001733.7 missense

Scores

9
5
3

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.07
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PS1
Transcript NM_001733.7 (C1R) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_001733.7
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.988
PP5
Variant 12-7088850-T-C is Pathogenic according to our data. Variant chr12-7088850-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 375577.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
C1RNM_001733.7 linkuse as main transcriptc.905A>G p.Tyr302Cys missense_variant 6/11 ENST00000647956.2
C1RNM_001354346.2 linkuse as main transcriptc.947A>G p.Tyr316Cys missense_variant 6/11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
C1RENST00000647956.2 linkuse as main transcriptc.905A>G p.Tyr302Cys missense_variant 6/11 NM_001733.7 P1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
0
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, periodontal type 2 Pathogenic:1
Likely pathogenic, no assertion criteria providedresearchUniversity of Washington Center for Mendelian Genomics, University of WashingtonOct 13, 2016- -
Ehlers-Danlos syndrome, periodontal type 1 Pathogenic:1
Pathogenic, criteria provided, single submitterresearchInstitute of Human Genetics, Medical University InnsbruckAug 23, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.92
BayesDel_addAF
Pathogenic
0.47
D
BayesDel_noAF
Pathogenic
0.44
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.023
.;.;T;T
Eigen
Uncertain
0.52
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;.;D;D
MetaRNN
Pathogenic
0.99
D;D;D;D
MetaSVM
Benign
-0.57
T
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.70
T
PROVEAN
Pathogenic
-8.2
.;.;D;D
REVEL
Pathogenic
0.66
Sift
Pathogenic
0.0
.;.;D;D
Sift4G
Pathogenic
0.0
.;.;D;.
Polyphen
1.0
.;.;D;D
Vest4
0.93, 0.93, 0.93
MutPred
0.89
Gain of methylation at K299 (P = 0.1143);Gain of methylation at K299 (P = 0.1143);.;.;
MVP
0.60
ClinPred
1.0
D
GERP RS
5.7
gMVP
0.96

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1057519576; hg19: chr12-7241446; API