NM_000064.4:c.1479+50C>T

Variant names:

• chr19-6710937-G-A
• rs10411506
• NM_000064.4:c.1479+50C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000064.4(C3):​c.1479+50C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 1,603,574 control chromosomes in the GnomAD database, including 19,069 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1909 hom., cov: 32)
  • Exomes 𝑓: 0.14 (17160 hom.)
• Consequence: C3 NM_000064.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.29
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 19-6710937-G-A is Benign according to our data. Variant chr19-6710937-G-A is described in ClinVar as Benign. ClinVar VariationId is 1230447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C3	NM_000064.4	c.1479+50C>T		intron_variant	Intron 12 of 40	ENST00000245907.11	NP_000055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11	c.1479+50C>T		intron_variant	Intron 12 of 40	1	NM_000064.4	ENSP00000245907.4

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22305 AN: 151966 Hom.: 1910 Cov.: 32

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.191

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.193

Gnomad EAS AF: 0.429

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.132

GnomAD2 exomes AF: 0.171 AC: 42750 AN: 250716 AF XY: 0.173

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.114

Gnomad ASJ exome AF: 0.196

Gnomad EAS exome AF: 0.428

Gnomad FIN exome AF: 0.195

Gnomad NFE exome AF: 0.132

Gnomad OTH exome AF: 0.164

GnomAD4 exome AF: 0.143 AC: 208199 AN: 1451490 Hom.: 17160 Cov.: 31 AF XY: 0.146 AC XY: 105363 AN XY: 722682

African (AFR) AF: 0.122 AC: 4047 AN: 33262

American (AMR) AF: 0.114 AC: 5092 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 5200 AN: 26058

East Asian (EAS) AF: 0.411 AC: 16277 AN: 39638

South Asian (SAS) AF: 0.217 AC: 18639 AN: 86016

European-Finnish (FIN) AF: 0.199 AC: 10596 AN: 53366

Middle Eastern (MID) AF: 0.127 AC: 726 AN: 5738

European-Non Finnish (NFE) AF: 0.125 AC: 138234 AN: 1102620

Other (OTH) AF: 0.156 AC: 9388 AN: 60086

GnomAD4 genome AF: 0.147 AC: 22305 AN: 152084 Hom.: 1909 Cov.: 32 AF XY: 0.153 AC XY: 11354 AN XY: 74344

African (AFR) AF: 0.121 AC: 5018 AN: 41484

American (AMR) AF: 0.126 AC: 1919 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 670 AN: 3466

East Asian (EAS) AF: 0.429 AC: 2213 AN: 5162

South Asian (SAS) AF: 0.253 AC: 1217 AN: 4812

European-Finnish (FIN) AF: 0.191 AC: 2025 AN: 10590

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.129 AC: 8760 AN: 67974

Other (OTH) AF: 0.130 AC: 274 AN: 2114

Alfa AF: 0.147 Hom.: 590

Bravo AF: 0.139

Asia WGS AF: 0.297 AC: 1031 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

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	-0.80
CADD	Benign	0.29
DANN	Benign	0.54
PhyloP100		-2.3
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs10411506; hg19: chr19-6710948; COSMIC: COSV55580076; COSMIC: COSV55580076;