rs17612

Positions:

• chr9-120963648-T-G

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.4311A>C​(p.Glu1437Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.061 in 1,610,638 control chromosomes in the GnomAD database, including 3,483 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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.

• Frequency:
  • Genomes: 𝑓 0.045 (230 hom., cov: 32)
  • Exomes 𝑓: 0.063 (3253 hom.)
• Consequence: C5 NM_001735.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.209

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=0.0017857254).
• BP6: Variant 9-120963648-T-G is Benign according to our data. Variant chr9-120963648-T-G is described in ClinVar as [Benign]. Clinvar id is 402451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0672 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C5	NM_001735.3	c.4311A>C	p.Glu1437Asp	missense_variant	34/41	ENST00000223642.3
C5	NM_001317163.2	c.4329A>C	p.Glu1443Asp	missense_variant	34/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C5	ENST00000223642.3	c.4311A>C	p.Glu1437Asp	missense_variant	34/41	1	NM_001735.3	P1

Frequencies

GnomAD3 genomes AF: 0.0454 AC: 6910 AN: 152210 Hom.: 230 Cov.: 32

Gnomad AFR AF: 0.0188

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0547

Gnomad ASJ AF: 0.0629

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0741

Gnomad FIN AF: 0.0132

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0649

Gnomad OTH AF: 0.0478

GnomAD3 exomes AF: 0.0537 AC: 13490 AN: 251280 Hom.: 474 AF XY: 0.0547 AC XY: 7429 AN XY: 135800

Gnomad AFR exome AF: 0.0191

Gnomad AMR exome AF: 0.0578

Gnomad ASJ exome AF: 0.0646

Gnomad EAS exome AF: 0.000870

Gnomad SAS exome AF: 0.0671

Gnomad FIN exome AF: 0.0152

Gnomad NFE exome AF: 0.0685

Gnomad OTH exome AF: 0.0570

GnomAD4 exome AF: 0.0626 AC: 91337 AN: 1458310 Hom.: 3253 Cov.: 30 AF XY: 0.0630 AC XY: 45745 AN XY: 725660

Gnomad4 AFR exome AF: 0.0181

Gnomad4 AMR exome AF: 0.0566

Gnomad4 ASJ exome AF: 0.0618

Gnomad4 EAS exome AF: 0.000731

Gnomad4 SAS exome AF: 0.0673

Gnomad4 FIN exome AF: 0.0168

Gnomad4 NFE exome AF: 0.0685

Gnomad4 OTH exome AF: 0.0597

GnomAD4 genome AF: 0.0453 AC: 6906 AN: 152328 Hom.: 230 Cov.: 32 AF XY: 0.0430 AC XY: 3202 AN XY: 74490

Gnomad4 AFR AF: 0.0189

Gnomad4 AMR AF: 0.0545

Gnomad4 ASJ AF: 0.0629

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0735

Gnomad4 FIN AF: 0.0132

Gnomad4 NFE AF: 0.0649

Gnomad4 OTH AF: 0.0473

Alfa AF: 0.0644 Hom.: 720

Bravo AF: 0.0472

TwinsUK AF: 0.0739 AC: 274

ALSPAC AF: 0.0667 AC: 257

ESP6500AA AF: 0.0229 AC: 101

ESP6500EA AF: 0.0698 AC: 600

ExAC AF: 0.0549 AC: 6662

Asia WGS AF: 0.0340 AC: 118 AN: 3478

EpiCase AF: 0.0701

EpiControl AF: 0.0711

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	5.4
DANN	Benign	0.96
DEOGEN2	Benign	0.079	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	0.76	D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.073
Sift	Benign	0.14	T
Sift4G	Benign	0.43	T
Polyphen		0.0020	B
Vest4		0.062
MutPred		0.26		Loss of ubiquitination at K1440 (P = 0.1741);
MPC		0.16
ClinPred		0.0035	T
GERP RS		-2.9
Varity_R		0.38
gMVP		0.53

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: rs17612; hg19: chr9-123725926; COSMIC: COSV56327119; COSMIC: COSV56327119;