rs25681

chr9-121017727-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001735.3(C5):c.1632C>T(p.Tyr544=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.443 in 1,611,088 control chromosomes in the GnomAD database, including 166,010 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (12470 hom., cov: 31)
  • Exomes 𝑓: 0.45 (153540 hom.)
• Consequence: C5 NM_001735.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• 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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 9-121017727-G-A is Benign according to our data. Variant chr9-121017727-G-A is described in ClinVar as [Benign]. Clinvar id is 402455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-121017727-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=3.5 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.607 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C5	NM_001735.3	c.1632C>T	p.Tyr544=	synonymous_variant	13/41	ENST00000223642.3
C5	NM_001317163.2	c.1650C>T	p.Tyr550=	synonymous_variant	13/41
C5	NM_001317164.2	c.1632C>T	p.Tyr544=	synonymous_variant	13/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C5	ENST00000223642.3	c.1632C>T	p.Tyr544=	synonymous_variant	13/41	1	NM_001735.3	P1

Frequencies

GnomAD3 genomes AF: 0.364 AC: 55249 AN: 151880 Hom.: 12457 Cov.: 31

Gnomad AFR AF: 0.0853

Gnomad AMI AF: 0.643

Gnomad AMR AF: 0.491

Gnomad ASJ AF: 0.521

Gnomad EAS AF: 0.558

Gnomad SAS AF: 0.623

Gnomad FIN AF: 0.509

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.436

Gnomad OTH AF: 0.408

GnomAD3 exomes AF: 0.470 AC: 118062 AN: 251256 Hom.: 29808 AF XY: 0.482 AC XY: 65476 AN XY: 135812

Gnomad AFR exome AF: 0.0729

Gnomad AMR exome AF: 0.547

Gnomad ASJ exome AF: 0.517

Gnomad EAS exome AF: 0.560

Gnomad SAS exome AF: 0.628

Gnomad FIN exome AF: 0.489

Gnomad NFE exome AF: 0.438

Gnomad OTH exome AF: 0.471

GnomAD4 exome AF: 0.451 AC: 657998 AN: 1459090 Hom.: 153540 Cov.: 33 AF XY: 0.457 AC XY: 332121 AN XY: 725974

Gnomad4 AFR exome AF: 0.0713

Gnomad4 AMR exome AF: 0.542

Gnomad4 ASJ exome AF: 0.512

Gnomad4 EAS exome AF: 0.533

Gnomad4 SAS exome AF: 0.629

Gnomad4 FIN exome AF: 0.485

Gnomad4 NFE exome AF: 0.439

Gnomad4 OTH exome AF: 0.447

GnomAD4 genome AF: 0.364 AC: 55262 AN: 151998 Hom.: 12470 Cov.: 31 AF XY: 0.374 AC XY: 27771 AN XY: 74302

Gnomad4 AFR AF: 0.0850

Gnomad4 AMR AF: 0.492

Gnomad4 ASJ AF: 0.521

Gnomad4 EAS AF: 0.559

Gnomad4 SAS AF: 0.625

Gnomad4 FIN AF: 0.509

Gnomad4 NFE AF: 0.435

Gnomad4 OTH AF: 0.409

Alfa AF: 0.409 Hom.: 10794

Bravo AF: 0.350

Asia WGS AF: 0.531 AC: 1846 AN: 3478

EpiCase AF: 0.446

EpiControl AF: 0.441

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 08, 2021	- -
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: MAF -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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
BayesDel_noAF	Benign	-0.55
Cadd	Benign	15
Dann	Benign	0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.26		Position offset: -11

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

Publications

LitVar

Other links and lift over

dbSNP: rs25681; hg19: chr9-123780005; COSMIC: COSV56324120;