rs17216529

Variant names:

Variant summary

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

The NM_001735.3(C5):c.433G>A(p.Val145Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0766 in 1,498,624 control chromosomes in the GnomAD database, including 6,267 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V145V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.12 ( 1652 hom., cov: 32)

Exomes 𝑓: 0.071 ( 4615 hom. )

Consequence

C5
NM_001735.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.61

Publications

24 publications found

Variant links:

Genes affected

C5 (HGNC:1331): (complement C5) This gene encodes a component of the complement system, a part of the innate immune system that plays an important role in inflammation, host homeostasis, and host defense against pathogens. The encoded preproprotein is proteolytically processed to generate multiple protein products, including the C5 alpha chain, C5 beta chain, C5a anaphylatoxin and C5b. The C5 protein is comprised of the C5 alpha and beta chains, which are linked by a disulfide bridge. Cleavage of the alpha chain by a convertase enzyme results in the formation of the C5a anaphylatoxin, which possesses potent spasmogenic and chemotactic activity, and the C5b macromolecular cleavage product, a subunit of the membrane attack complex (MAC). Mutations in this gene cause complement component 5 deficiency, a disease characterized by recurrent bacterial infections. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2015]

C5 Gene-Disease associations (from GenCC):

complement component 5 deficiency
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

C5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022572875).

BP6

Variant 9-121037940-C-T is Benign according to our data. Variant chr9-121037940-C-T is described in ClinVar as Benign. ClinVar VariationId is 1167059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C5	NM_001735.3 link	c.433G>A	p.Val145Ile	missense_variant	Exon 4 of 41	ENST00000223642.3	NP_001726.2	P01031
C5	NM_001317163.2 link	c.451G>A	p.Val151Ile	missense_variant	Exon 4 of 41		NP_001304092.1	P01031A0A8Q3SID6Q59GS8
C5	NM_001317164.2 link	c.433G>A	p.Val145Ile	missense_variant	Exon 4 of 21		NP_001304093.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C5	ENST00000223642.3 link	c.433G>A	p.Val145Ile	missense_variant	Exon 4 of 41	1	NM_001735.3	ENSP00000223642.1		P01031

Frequencies

GnomAD3 genomes

AF:

0.123

AC:

18643

AN:

151962

Hom.:

1650

Cov.:

show subpopulations

Gnomad AFR

AF:

0.247

Gnomad AMI

AF:

0.0680

Gnomad AMR

AF:

0.0596

Gnomad ASJ

AF:

0.0551

Gnomad EAS

AF:

0.186

Gnomad SAS

AF:

0.0348

Gnomad FIN

AF:

0.0692

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0764

Gnomad OTH

AF:

0.105

GnomAD2 exomes

AF:

0.0779

AC:

17595

AN:

225812

AF XY:

0.0731

show subpopulations

Gnomad AFR exome

AF:

0.249

Gnomad AMR exome

AF:

0.0367

Gnomad ASJ exome

AF:

0.0551

Gnomad EAS exome

AF:

0.166

Gnomad FIN exome

AF:

0.0732

Gnomad NFE exome

AF:

0.0703

Gnomad OTH exome

AF:

0.0692

GnomAD4 exome

AF:

0.0714

AC:

96080

AN:

1346544

Hom.:

4615

Cov.:

AF XY:

0.0701

AC XY:

47142

AN XY:

672146

show subpopulations

African (AFR)

AF:

0.242

AC:

7391

AN:

30506

American (AMR)

AF:

0.0407

AC:

1753

AN:

43048

Ashkenazi Jewish (ASJ)

AF:

0.0560

AC:

1373

AN:

24510

East Asian (EAS)

AF:

0.186

AC:

7144

AN:

38320

South Asian (SAS)

AF:

0.0296

AC:

2286

AN:

77108

European-Finnish (FIN)

AF:

0.0766

AC:

3878

AN:

50650

Middle Eastern (MID)

AF:

0.0385

AC:

197

AN:

5114

European-Non Finnish (NFE)

AF:

0.0662

AC:

67646

AN:

1021528

Other (OTH)

AF:

0.0791

AC:

4412

AN:

55760

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

3337

6675

10012

13350

16687

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2486

4972

7458

9944

12430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.123

AC:

18677

AN:

152080

Hom.:

1652

Cov.:

AF XY:

0.119

AC XY:

8830

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.247

AC:

10236

AN:

41458

American (AMR)

AF:

0.0595

AC:

910

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0551

AC:

191

AN:

3466

East Asian (EAS)

AF:

0.186

AC:

962

AN:

5180

South Asian (SAS)

AF:

0.0334

AC:

161

AN:

4824

European-Finnish (FIN)

AF:

0.0692

AC:

732

AN:

10572

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0764

AC:

5193

AN:

67980

Other (OTH)

AF:

0.105

AC:

221

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

805

1609

2414

3218

4023

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

202

404

606

808

1010

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0943

Hom.:

2385

Bravo

AF:

0.127

TwinsUK

AF:

0.0642

AC:

238

ALSPAC

AF:

0.0763

AC:

294

ESP6500AA

AF:

0.226

AC:

991

ESP6500EA

AF:

0.0717

AC:

612

ExAC

AF:

0.0774

AC:

9315

Asia WGS

AF:

0.129

AC:

448

AN:

3468

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 22, 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

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.092

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.75

MetaRNN

Benign

0.0023

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

PhyloP100

3.6

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.37

REVEL

Benign

0.23

Sift

Benign

0.13

Sift4G

Benign

0.23

Polyphen

0.91

Vest4

0.13

MPC

0.27

ClinPred

0.018

GERP RS

3.5

Varity_R

0.14

gMVP

0.32

Mutation Taster

=96/4

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over