rs993247

Positions:

• chr9-121022971-A-G
• chr9-121022971-A-T

Variant summary

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

The NM_001735.3(C5):​c.1116+433T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.376 in 151,690 control chromosomes in the GnomAD database, including 12,690 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 0.38 (12690 hom., cov: 31)
• Consequence: C5 NM_001735.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.56

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=-0.81).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.618 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C5	NM_001735.3	c.1116+433T>C		intron_variant		ENST00000223642.3
C5	NM_001317163.2	c.1134+433T>C		intron_variant
C5	NM_001317164.2	c.1116+433T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C5	ENST00000223642.3	c.1116+433T>C		intron_variant		1	NM_001735.3	P1

Frequencies

GnomAD3 genomes AF: 0.376 AC: 56995 AN: 151572 Hom.: 12676 Cov.: 31

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.644

Gnomad AMR AF: 0.495

Gnomad ASJ AF: 0.522

Gnomad EAS AF: 0.561

Gnomad SAS AF: 0.636

Gnomad FIN AF: 0.511

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.436

Gnomad OTH AF: 0.416

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

GnomAD4 genome AF: 0.376 AC: 57021 AN: 151690 Hom.: 12690 Cov.: 31 AF XY: 0.386 AC XY: 28624 AN XY: 74142

Gnomad4 AFR AF: 0.126

Gnomad4 AMR AF: 0.495

Gnomad4 ASJ AF: 0.522

Gnomad4 EAS AF: 0.561

Gnomad4 SAS AF: 0.637

Gnomad4 FIN AF: 0.511

Gnomad4 NFE AF: 0.436

Gnomad4 OTH AF: 0.417

Alfa AF: 0.439 Hom.: 9205

Bravo AF: 0.363

Asia WGS AF: 0.535 AC: 1861 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.4
DANN	Benign	0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs993247; hg19: chr9-123785249;