9-121017727-G-T

Variant names:

• chr9-121017727-G-T
• NM_001735.3:c.1632C>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001735.3(C5):​c.1632C>A​(p.Tyr544*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y544Y) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: C5 NM_001735.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.50

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C5	NM_001735.3	c.1632C>A	p.Tyr544*	stop_gained	Exon 13 of 41	ENST00000223642.3	NP_001726.2
C5	NM_001317163.2	c.1650C>A	p.Tyr550*	stop_gained	Exon 13 of 41		NP_001304092.1
C5	NM_001317164.2	c.1632C>A	p.Tyr544*	stop_gained	Exon 13 of 21		NP_001304093.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C5	ENST00000223642.3	c.1632C>A	p.Tyr544*	stop_gained	Exon 13 of 41	1	NM_001735.3	ENSP00000223642.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.87	D
Vest4		0.96
GERP RS		4.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-123780005;