rs17216529

Positions:

• chr9-121037940-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.61

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 Benign. Variant got -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 id 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/exons	MANE	UniProt
C5	NM_001735.3	c.433G>A	p.Val145Ile	missense_variant	4/41	ENST00000223642.3
C5	NM_001317163.2	c.451G>A	p.Val151Ile	missense_variant	4/41
C5	NM_001317164.2	c.433G>A	p.Val145Ile	missense_variant	4/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C5	ENST00000223642.3	c.433G>A	p.Val145Ile	missense_variant	4/41	1	NM_001735.3	P1

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18643 AN: 151962 Hom.: 1650 Cov.: 32

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

GnomAD3 exomes AF: 0.0779 AC: 17595 AN: 225812 Hom.: 1047 AF XY: 0.0731 AC XY: 8937 AN XY: 122290

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 SAS exome AF: 0.0290

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.: 21 AF XY: 0.0701 AC XY: 47142 AN XY: 672146

Gnomad4 AFR exome AF: 0.242

Gnomad4 AMR exome AF: 0.0407

Gnomad4 ASJ exome AF: 0.0560

Gnomad4 EAS exome AF: 0.186

Gnomad4 SAS exome AF: 0.0296

Gnomad4 FIN exome AF: 0.0766

Gnomad4 NFE exome AF: 0.0662

Gnomad4 OTH exome AF: 0.0791

GnomAD4 genome AF: 0.123 AC: 18677 AN: 152080 Hom.: 1652 Cov.: 32 AF XY: 0.119 AC XY: 8830 AN XY: 74330

Gnomad4 AFR AF: 0.247

Gnomad4 AMR AF: 0.0595

Gnomad4 ASJ AF: 0.0551

Gnomad4 EAS AF: 0.186

Gnomad4 SAS AF: 0.0334

Gnomad4 FIN AF: 0.0692

Gnomad4 NFE AF: 0.0764

Gnomad4 OTH AF: 0.105

Alfa AF: 0.0860 Hom.: 979

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

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.092	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	0.0074	P
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.23
Sift	Benign	0.13	T
Sift4G	Benign	0.23	T
Polyphen		0.91	P
Vest4		0.13
MPC		0.27
ClinPred		0.018	T
GERP RS		3.5
Varity_R		0.14
gMVP		0.32

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

Other links and lift over

dbSNP: rs17216529; hg19: chr9-123800218;