Genetic Variant C3:c.*94C>T (chr19-6677788-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.14

Variant links:

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
C3	NM_000064.4 link	c.*94C>T		3_prime_UTR_variant	Exon 41 of 41	ENST00000245907.11	NP_000055.2	P01024V9HWA9B4DR57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11 link	c.*94C>T		3_prime_UTR_variant	Exon 41 of 41	1	NM_000064.4	ENSP00000245907.4		P01024

Frequencies

GnomAD3 genomes

AF:

0.0532

AC:

8100

AN:

152152

Hom.:

245

Cov.:

show subpopulations

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.:

AF XY:

0.0447

AC XY:

29976

AN XY:

670818

show subpopulations

African (AFR)

AF:

0.0821

AC:

2553

AN:

31106

American (AMR)

AF:

0.0252

AC:

1072

AN:

42588

Ashkenazi Jewish (ASJ)

AF:

0.0426

AC:

1068

AN:

25082

East Asian (EAS)

AF:

0.00645

AC:

251

AN:

38894

South Asian (SAS)

AF:

0.0530

AC:

4371

AN:

82534

European-Finnish (FIN)

AF:

0.0582

AC:

2634

AN:

45268

Middle Eastern (MID)

AF:

0.0425

AC:

210

AN:

4942

European-Non Finnish (NFE)

AF:

0.0439

AC:

44525

AN:

1013532

Other (OTH)

AF:

0.0453

AC:

2555

AN:

56406

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

2949

5897

8846

11794

14743

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0534

AC:

8129

AN:

152270

Hom.:

251

Cov.:

AF XY:

0.0527

AC XY:

3923

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0845

AC:

3508

AN:

41528

American (AMR)

AF:

0.0339

AC:

519

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0424

AC:

147

AN:

3470

East Asian (EAS)

AF:

0.00694

AC:

AN:

5184

South Asian (SAS)

AF:

0.0489

AC:

236

AN:

4824

European-Finnish (FIN)

AF:

0.0559

AC:

593

AN:

10612

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0439

AC:

2988

AN:

68036

Other (OTH)

AF:

0.0408

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

392

784

1176

1568

1960

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0457

Hom.:

225

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

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

-0.82

CADD

Benign

1.0

(source)

DANN

Benign

0.95

PhyloP100

-1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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19-6677788-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over