9-120953805-G-T

Position:

• chr9-120953805-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001735.3(C5):​c.4826C>A​(p.Ala1609Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: C5 NM_001735.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.12

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.863

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C5	NM_001735.3	c.4826C>A	p.Ala1609Asp	missense_variant	40/41	ENST00000223642.3
C5	NM_001317163.2	c.4844C>A	p.Ala1615Asp	missense_variant	40/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C5	ENST00000223642.3	c.4826C>A	p.Ala1609Asp	missense_variant	40/41	1	NM_001735.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 21, 2023

The c.4826C>A (p.A1609D) alteration is located in exon 40 (coding exon 40) of the C5 gene. This alteration results from a C to A substitution at nucleotide position 4826, causing the alanine (A) at amino acid position 1609 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.025	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.88	T
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	0.75	N
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.27
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.99	D
Vest4		0.44
MutPred		0.78		Gain of ubiquitination at K1613 (P = 0.0472);
MVP		0.85
MPC		0.74
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.61
gMVP		0.80

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-123716083;