dbSNP rs780251209: C3:p.Gln1647His (chr19-6677933-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000064.4(C3):c.4941G>T(p.Gln1647His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q1647Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000037 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00033 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

C3
NM_000064.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.298

Publications

0 publications found

Variant links:

Genes affected

C3 (HGNC:1318): (complement C3) Complement component C3 plays a central role in the activation of complement system. Its activation is required for both classical and alternative complement activation pathways. The encoded preproprotein is proteolytically processed to generate alpha and beta subunits that form the mature protein, which is then further processed to generate numerous peptide products. The C3a peptide, also known as the C3a anaphylatoxin, modulates inflammation and possesses antimicrobial activity. Mutations in this gene are associated with atypical hemolytic uremic syndrome and age-related macular degeneration in human patients. [provided by RefSeq, Nov 2015]

C3 Gene-Disease associations (from GenCC):

atypical hemolytic-uremic syndrome with C3 anomaly
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
complement component 3 deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Laboratory for Molecular Medicine
C3 glomerulonephritis
Inheritance: AD Classification: MODERATE Submitted by: ClinGen

C3 links:

ENSG00000297005 (HGNC:):

ENSG00000297005 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1684317).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C3	NM_000064.4 link	c.4941G>T	p.Gln1647His	missense_variant	Exon 41 of 41	ENST00000245907.11	NP_000055.2	P01024V9HWA9B4DR57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11 link	c.4941G>T	p.Gln1647His	missense_variant	Exon 41 of 41	1	NM_000064.4	ENSP00000245907.4		P01024

Frequencies

GnomAD3 genomes

AF:

0.0000366

AC:

AN:

136666

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000822

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000101

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000162

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

247368

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000328

AC:

462

AN:

1410484

Hom.:

Cov.:

AF XY:

0.000326

AC XY:

229

AN XY:

701636

show subpopulations

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

African (AFR)

AF:

0.000159

AC:

AN:

31486

American (AMR)

AF:

0.00162

AC:

AN:

41302

Ashkenazi Jewish (ASJ)

AF:

0.000161

AC:

AN:

24866

East Asian (EAS)

AF:

0.000273

AC:

AN:

36608

South Asian (SAS)

AF:

0.000175

AC:

AN:

80006

European-Finnish (FIN)

AF:

0.000135

AC:

AN:

51976

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5600

European-Non Finnish (NFE)

AF:

0.000298

AC:

322

AN:

1080776

Other (OTH)

AF:

0.000570

AC:

AN:

57864

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.230

Heterozygous variant carriers

185

278

370

463

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000366

AC:

AN:

136784

Hom.:

Cov.:

AF XY:

0.0000149

AC XY:

AN XY:

66910

show subpopulations

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

African (AFR)

AF:

0.0000819

AC:

AN:

36618

American (AMR)

AF:

0.00

AC:

AN:

13796

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3134

East Asian (EAS)

AF:

0.00

AC:

AN:

4584

South Asian (SAS)

AF:

0.00

AC:

AN:

4160

European-Finnish (FIN)

AF:

0.000101

AC:

AN:

9864

Middle Eastern (MID)

AF:

0.00

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.0000162

AC:

AN:

61658

Other (OTH)

AF:

0.00

AC:

AN:

1822

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.235

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.098

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.12

T;T

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.69

T;T

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

M;.

PhyloP100

0.30

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.6

N;.

REVEL

Benign

0.080

Sift

Benign

0.11

T;.

Sift4G

Benign

0.12

T;T

Polyphen

0.37

B;.

Vest4

0.16

MutPred

0.34

Gain of catalytic residue at L1649 (P = 0.0601);.;

MVP

0.75

MPC

0.67

ClinPred

0.24

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.21

gMVP

0.50

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs780251209

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over