9-121009521-T-C

Position:

• chr9-121009521-T-C

Variant summary

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

The NM_001735.3(C5):​c.2258-1023A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 152,252 control chromosomes in the GnomAD database, including 883 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 0.10 (883 hom., cov: 33)
• Consequence: C5 NM_001735.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.857

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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C5	NM_001735.3	c.2258-1023A>G		intron_variant		ENST00000223642.3	NP_001726.2
C5	NM_001317163.2	c.2276-1023A>G		intron_variant			NP_001304092.1
C5	NM_001317164.2	c.2258-1023A>G		intron_variant			NP_001304093.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C5	ENST00000223642.3	c.2258-1023A>G		intron_variant		1	NM_001735.3	ENSP00000223642	P1

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15932 AN: 152134 Hom.: 883 Cov.: 33

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.0352

Gnomad AMR AF: 0.0763

Gnomad ASJ AF: 0.0590

Gnomad EAS AF: 0.0325

Gnomad SAS AF: 0.0911

Gnomad FIN AF: 0.0626

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.0817

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

GnomAD4 genome AF: 0.105 AC: 15935 AN: 152252 Hom.: 883 Cov.: 33 AF XY: 0.102 AC XY: 7607 AN XY: 74450

Gnomad4 AFR AF: 0.137

Gnomad4 AMR AF: 0.0760

Gnomad4 ASJ AF: 0.0590

Gnomad4 EAS AF: 0.0322

Gnomad4 SAS AF: 0.0911

Gnomad4 FIN AF: 0.0626

Gnomad4 NFE AF: 0.109

Gnomad4 OTH AF: 0.0814

Alfa AF: 0.106 Hom.: 1197

Bravo AF: 0.106

Asia WGS AF: 0.0670 AC: 233 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.52
DANN	Benign	0.42

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: rs7027797; hg19: chr9-123771799;