9-120970855-A-C

Position:

• chr9-120970855-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001735.3(C5):​c.4081-604T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 152,100 control chromosomes in the GnomAD database, including 7,612 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.28 (7612 hom., cov: 32)
• Consequence: C5 NM_001735.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.28

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.509 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C5	NM_001735.3	c.4081-604T>G		intron_variant		ENST00000223642.3
C5	NM_001317163.2	c.4099-604T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C5	ENST00000223642.3	c.4081-604T>G		intron_variant		1	NM_001735.3	P1

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42125 AN: 151982 Hom.: 7589 Cov.: 32

Gnomad AFR AF: 0.515

Gnomad AMI AF: 0.266

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.246

Gnomad SAS AF: 0.135

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.231

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.277 AC: 42195 AN: 152100 Hom.: 7612 Cov.: 32 AF XY: 0.270 AC XY: 20047 AN XY: 74354

Gnomad4 AFR AF: 0.515

Gnomad4 AMR AF: 0.164

Gnomad4 ASJ AF: 0.130

Gnomad4 EAS AF: 0.245

Gnomad4 SAS AF: 0.133

Gnomad4 FIN AF: 0.155

Gnomad4 NFE AF: 0.200

Gnomad4 OTH AF: 0.231

Alfa AF: 0.203 Hom.: 4705

Bravo AF: 0.289

Asia WGS AF: 0.231 AC: 802 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.57
DANN	Benign	0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs7026551; hg19: chr9-123733133;