chr9-121037940-C-T

Variant names:

• chr9-121037940-C-T
• rs17216529
• NM_001735.3:c.433G>A

Variant summary

Our verdict is Benign. The variant received -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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). 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
• Publications: 24 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C5	NM_001735.3	MANE Select	c.433G>A	p.Val145Ile	missense	Exon 4 of 41	NP_001726.2
	C5	NM_001317163.2		c.451G>A	p.Val151Ile	missense	Exon 4 of 41	NP_001304092.1
	C5	NM_001317164.2		c.433G>A	p.Val145Ile	missense	Exon 4 of 21	NP_001304093.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C5	ENST00000223642.3	TSL:1 MANE Select	c.433G>A	p.Val145Ile	missense	Exon 4 of 41	ENSP00000223642.1
	C5	ENST00000696281.1		c.451G>A	p.Val151Ile	missense	Exon 4 of 42	ENSP00000512521.1
	C5	ENST00000696279.1		n.*806G>A		non_coding_transcript_exon	Exon 6 of 43	ENSP00000512520.1

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

GnomAD2 exomes AF: 0.0779 AC: 17595 AN: 225812 AF XY: 0.0731

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 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

African (AFR) AF: 0.242 AC: 7391 AN: 30506

American (AMR) AF: 0.0407 AC: 1753 AN: 43048

Ashkenazi Jewish (ASJ) AF: 0.0560 AC: 1373 AN: 24510

East Asian (EAS) AF: 0.186 AC: 7144 AN: 38320

South Asian (SAS) AF: 0.0296 AC: 2286 AN: 77108

European-Finnish (FIN) AF: 0.0766 AC: 3878 AN: 50650

Middle Eastern (MID) AF: 0.0385 AC: 197 AN: 5114

European-Non Finnish (NFE) AF: 0.0662 AC: 67646 AN: 1021528

Other (OTH) AF: 0.0791 AC: 4412 AN: 55760

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

African (AFR) AF: 0.247 AC: 10236 AN: 41458

American (AMR) AF: 0.0595 AC: 910 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0551 AC: 191 AN: 3466

East Asian (EAS) AF: 0.186 AC: 962 AN: 5180

South Asian (SAS) AF: 0.0334 AC: 161 AN: 4824

European-Finnish (FIN) AF: 0.0692 AC: 732 AN: 10572

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0764 AC: 5193 AN: 67980

Other (OTH) AF: 0.105 AC: 221 AN: 2108

Alfa AF: 0.0943 Hom.: 2385

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

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		3.6
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
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17216529; hg19: chr9-123800218; COSMIC: COSV107302684; COSMIC: COSV107302684;