rs7951

Variant names:

• chr19-6681980-G-A
• rs7951
• NM_000064.4:c.4311C>T

Variant summary

Our verdict is Benign. The variant received -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:8
• Conservation: PhyloP100: -0.297
• Publications: 28 publications found

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: ClinGen, Labcorp Genetics (formerly Invitae)
• complement component 3 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet
• C3 glomerulonephritis

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ENSG00000297005 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 330285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000064.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C3	NM_000064.4	MANE Select	c.4311C>T	p.Ala1437Ala	synonymous	Exon 35 of 41	NP_000055.2	P01024

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C3	ENST00000245907.11	TSL:1 MANE Select	c.4311C>T	p.Ala1437Ala	synonymous	Exon 35 of 41	ENSP00000245907.4	P01024
	C3	ENST00000952696.1		c.4323C>T	p.Ala1441Ala	synonymous	Exon 36 of 42	ENSP00000622755.1
	C3	ENST00000879543.1		c.4308C>T	p.Ala1436Ala	synonymous	Exon 35 of 41	ENSP00000549602.1

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

GnomAD2 exomes AF: 0.0840 AC: 21130 AN: 251496 AF XY: 0.0848

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 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

African (AFR) AF: 0.0928 AC: 3107 AN: 33470

American (AMR) AF: 0.0578 AC: 2587 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0939 AC: 2453 AN: 26132

East Asian (EAS) AF: 0.0927 AC: 3681 AN: 39696

South Asian (SAS) AF: 0.0951 AC: 8201 AN: 86236

European-Finnish (FIN) AF: 0.118 AC: 6326 AN: 53420

Middle Eastern (MID) AF: 0.0839 AC: 483 AN: 5756

European-Non Finnish (NFE) AF: 0.0735 AC: 81721 AN: 1111494

Other (OTH) AF: 0.0815 AC: 4924 AN: 60382

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

African (AFR) AF: 0.0953 AC: 3958 AN: 41536

American (AMR) AF: 0.0738 AC: 1128 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0936 AC: 325 AN: 3472

East Asian (EAS) AF: 0.0970 AC: 502 AN: 5176

South Asian (SAS) AF: 0.0961 AC: 463 AN: 4820

European-Finnish (FIN) AF: 0.109 AC: 1157 AN: 10606

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0768 AC: 5222 AN: 68004

Other (OTH) AF: 0.0808 AC: 171 AN: 2116

Alfa AF: 0.0774 Hom.: 755

Bravo AF: 0.0830

Asia WGS AF: 0.0870 AC: 304 AN: 3478

EpiCase AF: 0.0747

EpiControl AF: 0.0757

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Age related macular degeneration 9 (1)
-	-	1	Atypical hemolytic-uremic syndrome with C3 anomaly (1)
-	-	1	Atypical hemolytic-uremic syndrome;C3151071:Complement component 3 deficiency;C4055342:C3 glomerulonephritis (1)
-	-	1	Complement component 3 deficiency (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.7
DANN	Benign	0.44
PhyloP100		-0.30
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

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