12-7090144-C-G

Position:

chr12-7090144-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001733.7(C1R):c.336G>C(p.Met112Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0032 in 775,160 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M112V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0027 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0033 ( 8 hom. )

Consequence

C1R
NM_001733.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 4.89

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]

C1R links:

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]

C1RL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009718746).

BP6

Variant 12-7090144-C-G is Benign according to our data. Variant chr12-7090144-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 625897.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High AC in GnomAd4 at 411 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C1R	NM_001733.7 linkuse as main transcript	c.336G>C	p.Met112Ile	missense_variant	3/11	ENST00000647956.2
C1R	NM_001354346.2 linkuse as main transcript	c.378G>C	p.Met126Ile	missense_variant	3/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C1R	ENST00000647956.2 linkuse as main transcript	c.336G>C	p.Met112Ile	missense_variant	3/11		NM_001733.7	P1

Frequencies

GnomAD3 genomes

AF:

0.00270

AC:

411

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000845

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00216

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00428

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.00282

AC:

673

AN:

238918

Hom.:

AF XY:

0.00257

AC XY:

333

AN XY:

129332

show subpopulations

Gnomad AFR exome

AF:

0.000627

Gnomad AMR exome

AF:

0.00264

Gnomad ASJ exome

AF:

0.000307

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00185

Gnomad NFE exome

AF:

0.00471

Gnomad OTH exome

AF:

0.00408

GnomAD4 exome

AF:

0.00332

AC:

2069

AN:

622826

Hom.:

Cov.:

AF XY:

0.00307

AC XY:

1042

AN XY:

338900

show subpopulations

Gnomad4 AFR exome

AF:

0.000965

Gnomad4 AMR exome

AF:

0.00273

Gnomad4 ASJ exome

AF:

0.000240

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000146

Gnomad4 FIN exome

AF:

0.00223

Gnomad4 NFE exome

AF:

0.00479

Gnomad4 OTH exome

AF:

0.00413

GnomAD4 genome

AF:

0.00270

AC:

411

AN:

152334

Hom.:

Cov.:

AF XY:

0.00259

AC XY:

193

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000842

Gnomad4 AMR

AF:

0.00333

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00216

Gnomad4 NFE

AF:

0.00428

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00395

Hom.:

Bravo

AF:

0.00274

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.00103

AC:

ESP6500EA

AF:

0.00435

AC:

ExAC

AF:

0.00273

AC:

330

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Vascular dementia

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Myllykangas group, University of Helsinki

Apr 01, 2020

- -

Ehlers-Danlos syndrome, periodontal type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

C1R NM_001733.4 exon 5 p.Met112Ile (c.336G>C): This variant has not been reported in the literature but is present in 0.4% (564/121832) of European alleles, including 1 homozygote, in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs139531404). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Benign

-0.086

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

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

0.83

LIST_S2

Uncertain

0.88

D;.;D;T;D;T;D;D;D

MetaRNN

Benign

0.0089

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.63

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-2.8

.;.;D;N;D;D;D;N;D

REVEL

Uncertain

0.32

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

0.038

GERP RS

5.4

gMVP

0.41

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over