rs2230205

Positions:

chr19-6709693-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000064.4(C3):c.1836G>A(p.Thr612=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,612,072 control chromosomes in the GnomAD database, including 19,538 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 1934 hom., cov: 28)

Exomes 𝑓: 0.14 ( 17604 hom. )

Consequence

C3
NM_000064.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.27

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 19-6709693-C-T is Benign according to our data. Variant chr19-6709693-C-T is described in ClinVar as [Benign]. Clinvar id is 330317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.27 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.42 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C3	NM_000064.4 linkuse as main transcript	c.1836G>A	p.Thr612=	synonymous_variant	14/41	ENST00000245907.11	NP_000055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11 linkuse as main transcript	c.1836G>A	p.Thr612=	synonymous_variant	14/41	1	NM_000064.4	ENSP00000245907	P1

Frequencies

GnomAD3 genomes

AF:

0.147

AC:

22262

AN:

151292

Hom.:

1932

Cov.:

show subpopulations

Gnomad AFR

AF:

0.120

Gnomad AMI

AF:

0.191

Gnomad AMR

AF:

0.126

Gnomad ASJ

AF:

0.194

Gnomad EAS

AF:

0.435

Gnomad SAS

AF:

0.260

Gnomad FIN

AF:

0.192

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.129

Gnomad OTH

AF:

0.132

GnomAD3 exomes

AF:

0.172

AC:

43146

AN:

251408

Hom.:

4638

AF XY:

0.175

AC XY:

23748

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.118

Gnomad AMR exome

AF:

0.115

Gnomad ASJ exome

AF:

0.196

Gnomad EAS exome

AF:

0.432

Gnomad SAS exome

AF:

0.232

Gnomad FIN exome

AF:

0.193

Gnomad NFE exome

AF:

0.132

Gnomad OTH exome

AF:

0.166

GnomAD4 exome

AF:

0.145

AC:

211286

AN:

1460662

Hom.:

17604

Cov.:

AF XY:

0.147

AC XY:

107013

AN XY:

726650

show subpopulations

Gnomad4 AFR exome

AF:

0.122

Gnomad4 AMR exome

AF:

0.114

Gnomad4 ASJ exome

AF:

0.200

Gnomad4 EAS exome

AF:

0.417

Gnomad4 SAS exome

AF:

0.225

Gnomad4 FIN exome

AF:

0.197

Gnomad4 NFE exome

AF:

0.126

Gnomad4 OTH exome

AF:

0.158

GnomAD4 genome

AF:

0.147

AC:

22278

AN:

151410

Hom.:

1934

Cov.:

AF XY:

0.153

AC XY:

11333

AN XY:

73902

show subpopulations

Gnomad4 AFR

AF:

0.121

Gnomad4 AMR

AF:

0.125

Gnomad4 ASJ

AF:

0.194

Gnomad4 EAS

AF:

0.435

Gnomad4 SAS

AF:

0.260

Gnomad4 FIN

AF:

0.192

Gnomad4 NFE

AF:

0.129

Gnomad4 OTH

AF:

0.129

Alfa

AF:

0.135

Hom.:

2218

Bravo

AF:

0.140

Asia WGS

AF:

0.303

AC:

1051

AN:

3478

EpiCase

AF:

0.128

EpiControl

AF:

0.125

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Age related macular degeneration 9

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Complement component 3 deficiency

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Atypical hemolytic-uremic syndrome with C3 anomaly

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

3.4

DANN

Benign

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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