chr19-6677788-G-A

Position:

• chr19-6677788-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000064.4(C3):​c.*94C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0451 in 1,492,622 control chromosomes in the GnomAD database, including 1,733 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (251 hom., cov: 32)
  • Exomes 𝑓: 0.044 (1482 hom.)
• Consequence: C3 NM_000064.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.14

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 19-6677788-G-A is Benign according to our data. Variant chr19-6677788-G-A is described in ClinVar as [Benign]. Clinvar id is 1280962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0821 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C3	NM_000064.4	c.*94C>T		3_prime_UTR_variant	41/41	ENST00000245907.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C3	ENST00000245907.11	c.*94C>T		3_prime_UTR_variant	41/41	1	NM_000064.4	P1
C3	ENST00000695651.1	n.3434C>T		non_coding_transcript_exon_variant	28/28
C3	ENST00000601475.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0532 AC: 8100 AN: 152152 Hom.: 245 Cov.: 32

Gnomad AFR AF: 0.0839

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0340

Gnomad ASJ AF: 0.0424

Gnomad EAS AF: 0.00693

Gnomad SAS AF: 0.0493

Gnomad FIN AF: 0.0559

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0439

Gnomad OTH AF: 0.0407

GnomAD4 exome AF: 0.0442 AC: 59239 AN: 1340352 Hom.: 1482 Cov.: 20 AF XY: 0.0447 AC XY: 29976 AN XY: 670818

Gnomad4 AFR exome AF: 0.0821

Gnomad4 AMR exome AF: 0.0252

Gnomad4 ASJ exome AF: 0.0426

Gnomad4 EAS exome AF: 0.00645

Gnomad4 SAS exome AF: 0.0530

Gnomad4 FIN exome AF: 0.0582

Gnomad4 NFE exome AF: 0.0439

Gnomad4 OTH exome AF: 0.0453

GnomAD4 genome AF: 0.0534 AC: 8129 AN: 152270 Hom.: 251 Cov.: 32 AF XY: 0.0527 AC XY: 3923 AN XY: 74452

Gnomad4 AFR AF: 0.0845

Gnomad4 AMR AF: 0.0339

Gnomad4 ASJ AF: 0.0424

Gnomad4 EAS AF: 0.00694

Gnomad4 SAS AF: 0.0489

Gnomad4 FIN AF: 0.0559

Gnomad4 NFE AF: 0.0439

Gnomad4 OTH AF: 0.0408

Alfa AF: 0.0442 Hom.: 159

Bravo AF: 0.0527

Asia WGS AF: 0.0350 AC: 120 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.0
DANN	Benign	0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs11569585; hg19: chr19-6677799;