rs7951

Positions:

• chr19-6681980-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000064.4(C3):​c.4311C>T​(p.Ala1437Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0784 in 1,613,528 control chromosomes in the GnomAD database, including 5,204 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.086 (574 hom., cov: 32)
  • Exomes 𝑓: 0.078 (4630 hom.)
• Consequence: C3 NM_000064.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.297

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-6681980-G-A is Benign according to our data. Variant chr19-6681980-G-A is described in ClinVar as [Benign]. Clinvar id is 330285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-6681980-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.297 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0928 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C3	NM_000064.4	c.4311C>T	p.Ala1437Ala	synonymous_variant	35/41	ENST00000245907.11	NP_000055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11	c.4311C>T	p.Ala1437Ala	synonymous_variant	35/41	1	NM_000064.4	ENSP00000245907.4

Frequencies

GnomAD3 genomes AF: 0.0856 AC: 13013 AN: 152100 Hom.: 568 Cov.: 32

Gnomad AFR AF: 0.0947

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.0738

Gnomad ASJ AF: 0.0936

Gnomad EAS AF: 0.0975

Gnomad SAS AF: 0.0960

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0768

Gnomad OTH AF: 0.0778

GnomAD3 exomes AF: 0.0840 AC: 21130 AN: 251496 Hom.: 975 AF XY: 0.0848 AC XY: 11528 AN XY: 135922

Gnomad AFR exome AF: 0.0955

Gnomad AMR exome AF: 0.0559

Gnomad ASJ exome AF: 0.0912

Gnomad EAS exome AF: 0.105

Gnomad SAS exome AF: 0.0955

Gnomad FIN exome AF: 0.121

Gnomad NFE exome AF: 0.0768

Gnomad OTH exome AF: 0.0847

GnomAD4 exome AF: 0.0777 AC: 113483 AN: 1461310 Hom.: 4630 Cov.: 31 AF XY: 0.0785 AC XY: 57079 AN XY: 727008

Gnomad4 AFR exome AF: 0.0928

Gnomad4 AMR exome AF: 0.0578

Gnomad4 ASJ exome AF: 0.0939

Gnomad4 EAS exome AF: 0.0927

Gnomad4 SAS exome AF: 0.0951

Gnomad4 FIN exome AF: 0.118

Gnomad4 NFE exome AF: 0.0735

Gnomad4 OTH exome AF: 0.0815

GnomAD4 genome AF: 0.0857 AC: 13051 AN: 152218 Hom.: 574 Cov.: 32 AF XY: 0.0869 AC XY: 6465 AN XY: 74436

Gnomad4 AFR AF: 0.0953

Gnomad4 AMR AF: 0.0738

Gnomad4 ASJ AF: 0.0936

Gnomad4 EAS AF: 0.0970

Gnomad4 SAS AF: 0.0961

Gnomad4 FIN AF: 0.109

Gnomad4 NFE AF: 0.0768

Gnomad4 OTH AF: 0.0808

Alfa AF: 0.0765 Hom.: 609

Bravo AF: 0.0830

Asia WGS AF: 0.0870 AC: 304 AN: 3478

EpiCase AF: 0.0747

EpiControl AF: 0.0757

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 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: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. -

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. -

Complement component 3 deficiency 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	-0.81
CADD	Benign	2.7
DANN	Benign	0.44

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

Other links and lift over

dbSNP: rs7951; hg19: chr19-6681991; COSMIC: COSV55573596; COSMIC: COSV55573596;