rs121909587

Positions:

chr9-121050192-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong

The NM_001735.3(C5):c.55C>T(p.Gln19*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000793 in 1,613,268 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 1 hom. )

Consequence

C5
NM_001735.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 5.79

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 links:

C5 (HGNC:):

C5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.989 CDS is truncated, and there are 1 pathogenic variants in the truncated region.

PP5

Variant 9-121050192-G-A is Pathogenic according to our data. Variant chr9-121050192-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C5	NM_001735.3 linkuse as main transcript	c.55C>T	p.Gln19*	stop_gained	1/41	ENST00000223642.3	NP_001726.2	P01031
C5	NM_001317164.2 linkuse as main transcript	c.55C>T	p.Gln19*	stop_gained	1/21		NP_001304093.1
C5	NM_001317163.2 linkuse as main transcript	c.84-3809C>T		intron_variant			NP_001304092.1	P01031A0A8Q3SID6Q59GS8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C5	ENST00000223642.3 linkuse as main transcript	c.55C>T	p.Gln19*	stop_gained	1/41	1	NM_001735.3	ENSP00000223642.1		P01031

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00140

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000139

AC:

AN:

251162

Hom.:

AF XY:

0.0000737

AC XY:

AN XY:

135752

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000465

AC:

AN:

1460998

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

726854

show subpopulations

Gnomad4 AFR exome

AF:

0.00149

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000394

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.00142

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000158

Hom.:

Bravo

AF:

0.000453

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000107

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Complement component 5 deficiency

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 28, 2017	The p.Gln19X variant in C5 has been reported in 3 families with C5 complement deficiency. In 1 family, the 2 affected members carried the variant in the homozygous state (Arnaout 2013), whereas in the remaining 2 families (Wang 1995, reported as(C84 AG to TAG) ) the variant was found in the heterozygous state in 6 affected individuals (presumably a second undetected variant was present on the other allele) . This variant has also been identified in 0.12% (29/24,032) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121909587). This nonsense variant leads to a premature termination codon at position 19, which is predicted to lead to a truncated or absent protein. In summary, this variant meets criteria to be classified as pathogenic for C5 complement deficiency in an autosomal recessive manner based upon biallelic case observations, segregation studies and the nature of the variant (nonsense). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 16, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 15, 1995	- -

Complement component 5 deficiency;C3810402:Eculizumab, poor response to

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jun 30, 2021

- -

Lathosterolosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 14, 2024

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 04, 2024

This sequence change creates a premature translational stop signal (p.Gln19*) in the C5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in C5 are known to be pathogenic (PMID: 7730648, 19414197, 27026170). This variant is present in population databases (rs121909587, gnomAD 0.1%). This premature translational stop signal has been observed in individual(s) with C5 deficiency and C5 deficiency in a family and has also been reported in individuals affected with C5 deficiency, including in the compound heterozygous state (PMID: 7730648, 23371790, 25534848). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Q1X. ClinVar contains an entry for this variant (Variation ID: 17050). For these reasons, this variant has been classified as Pathogenic. -

C5-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 17, 2024

The C5 c.55C>T variant is predicted to result in premature protein termination (p.Gln19*). This variant has been reported in the homozygous or compound heterozygous states in patients with C5 deficiency (Arnaout et al. 2013. PubMed ID: 23371790). This variant is reported in 0.13% of alleles in individuals of African descent in gnomAD. Nonsense variants in C5 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Uncertain

0.82

Vest4

0.72

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over