chr19-6677927-G-A

Variant names:

• chr19-6677927-G-A
• rs377762182
• NM_000064.4:c.4947C>T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_000064.4(C3):​c.4947C>T​(p.Leu1649Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000387 in 1,603,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: C3 NM_000064.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.686

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 19-6677927-G-A is Benign according to our data. Variant chr19-6677927-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2069494.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-0.686 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000201 (29/144454) while in subpopulation AFR AF= 0.000718 (28/38986). AF 95% confidence interval is 0.00051. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C3	NM_000064.4	c.4947C>T	p.Leu1649Leu	synonymous_variant	Exon 41 of 41	ENST00000245907.11	NP_000055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11	c.4947C>T	p.Leu1649Leu	synonymous_variant	Exon 41 of 41	1	NM_000064.4	ENSP00000245907.4

Frequencies

GnomAD3 genomes AF: 0.000201 AC: 29 AN: 144336 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000720

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000688

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000518 AC: 13 AN: 251020 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135676

Gnomad AFR exome AF: 0.000801

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1458798 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 725728

Gnomad4 AFR exome AF: 0.000929

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.000201 AC: 29 AN: 144454 Hom.: 0 Cov.: 31 AF XY: 0.000255 AC XY: 18 AN XY: 70546

Gnomad4 AFR AF: 0.000718

Gnomad4 AMR AF: 0.0000687

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000263 Hom.: 0

Bravo AF: 0.000268

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Age related macular degeneration 9;C2752037:Atypical hemolytic-uremic syndrome with C3 anomaly;C3151071:Complement component 3 deficiency Uncertain:1

Oct 05, 2022

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF 0.07% (28/38864) (https://gnomad.broadinstitute.org/variant/19-6677927-G-A?dataset=gnomad_r3). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant is a silent variant and does not change the amino acid, reducing the probability that this variant is disease causing. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not provided Benign:1

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.1
DANN	Benign	0.77

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

LitVar

Other links and lift over

dbSNP: rs377762182; hg19: chr19-6677938; COSMIC: COSV99837089; COSMIC: COSV99837089;