chr19-6690971-C-G

Variant names:

• chr19-6690971-C-G
• rs3745565
• NM_000064.4:c.3391-244G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000064.4(C3):​c.3391-244G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 152,022 control chromosomes in the GnomAD database, including 1,010 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.11 (1010 hom., cov: 32)
• Consequence: C3 NM_000064.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.113
• Publications: 9 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: Labcorp Genetics (formerly Invitae), ClinGen
• complement component 3 deficiency

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

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 19-6690971-C-G is Benign according to our data. Variant chr19-6690971-C-G is described in ClinVar as Benign. ClinVar VariationId is 1178537.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C3	NM_000064.4	c.3391-244G>C		intron_variant	Intron 26 of 40	ENST00000245907.11	NP_000055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11	c.3391-244G>C		intron_variant	Intron 26 of 40	1	NM_000064.4	ENSP00000245907.4

Frequencies

GnomAD3 genomes AF: 0.105 AC: 16008 AN: 151910 Hom.: 1009 Cov.: 32

Gnomad AFR AF: 0.0559

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.0997

Gnomad ASJ AF: 0.182

Gnomad EAS AF: 0.0756

Gnomad SAS AF: 0.0789

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.0541

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.119

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.105 AC: 16018 AN: 152022 Hom.: 1010 Cov.: 32 AF XY: 0.106 AC XY: 7883 AN XY: 74316

African (AFR) AF: 0.0559 AC: 2318 AN: 41494

American (AMR) AF: 0.0995 AC: 1518 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 631 AN: 3472

East Asian (EAS) AF: 0.0752 AC: 389 AN: 5174

South Asian (SAS) AF: 0.0797 AC: 384 AN: 4820

European-Finnish (FIN) AF: 0.175 AC: 1844 AN: 10542

Middle Eastern (MID) AF: 0.0582 AC: 17 AN: 292

European-Non Finnish (NFE) AF: 0.125 AC: 8524 AN: 67958

Other (OTH) AF: 0.119 AC: 251 AN: 2106

Alfa AF: 0.114 Hom.: 145

Bravo AF: 0.0991

Asia WGS AF: 0.0800 AC: 279 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 18, 2021

GeneDx

Significance: 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	-0.86
CADD	Benign	4.1
DANN	Benign	0.50
PhyloP100		0.11
PromoterAI		0.0026	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3745565; hg19: chr19-6690982;