Genetic Variant C5:c.3659-1301G>A (chr9-120978206-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001735.3(C5):c.3659-1301G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 151,900 control chromosomes in the GnomAD database, including 12,569 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.40 ( 12569 hom., cov: 32)

Consequence

C5
NM_001735.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.110

Publications

22 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.6 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001735.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C5	NM_001735.3	MANE Select	c.3659-1301G>A		intron	N/A	NP_001726.2
	C5	NM_001317163.2		c.3677-1301G>A		intron	N/A	NP_001304092.1	A0A8Q3SID6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
C5	ENST00000223642.3	TSL:1 MANE Select	c.3659-1301G>A	intron	N/A	ENSP00000223642.1	P01031
C5	ENST00000696281.1		c.3677-1301G>A	intron	N/A	ENSP00000512521.1	A0A8Q3SID6
C5	ENST00000867873.1		c.3659-1301G>A	intron	N/A	ENSP00000537932.1

Frequencies

GnomAD3 genomes

AF:

0.396

AC:

60099

AN:

151782

Hom.:

12554

Cov.:

show subpopulations

Gnomad AFR

AF:

0.261

Gnomad AMI

AF:

0.337

Gnomad AMR

AF:

0.489

Gnomad ASJ

AF:

0.505

Gnomad EAS

AF:

0.557

Gnomad SAS

AF:

0.617

Gnomad FIN

AF:

0.482

Gnomad MID

AF:

0.468

Gnomad NFE

AF:

0.410

Gnomad OTH

AF:

0.424

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

GnomAD4 genome

AF:

0.396

AC:

60148

AN:

151900

Hom.:

12569

Cov.:

AF XY:

0.406

AC XY:

30124

AN XY:

74246

show subpopulations

African (AFR)

AF:

0.261

AC:

10805

AN:

41424

American (AMR)

AF:

0.490

AC:

7482

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.505

AC:

1749

AN:

3464

East Asian (EAS)

AF:

0.558

AC:

2887

AN:

5178

South Asian (SAS)

AF:

0.619

AC:

2982

AN:

4820

European-Finnish (FIN)

AF:

0.482

AC:

5062

AN:

10510

Middle Eastern (MID)

AF:

0.463

AC:

136

AN:

294

European-Non Finnish (NFE)

AF:

0.410

AC:

27840

AN:

67920

Other (OTH)

AF:

0.426

AC:

898

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1845

3690

5535

7380

9225

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

580

1160

1740

2320

2900

<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:

0.421

Hom.:

12380

Bravo

AF:

0.388

Asia WGS

AF:

0.541

AC:

1868

AN:

3458

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

1.4

(source)

DANN

Benign

0.74

PhyloP100

-0.11

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over