9-121047612-C-T

Variant names:

• chr9-121047612-C-T
• rs1468673
• NM_001735.3:c.66-1229G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001735.3(C5):​c.66-1229G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.514 in 152,108 control chromosomes in the GnomAD database, including 22,455 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 0.51 (22455 hom., cov: 32)
• Consequence: C5 NM_001735.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.308
• Publications: 21 publications found

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]

C5 Gene-Disease associations (from GenCC):

• complement component 5 deficiency

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.768 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C5	NM_001735.3	c.66-1229G>A		intron_variant	Intron 1 of 40	ENST00000223642.3	NP_001726.2
C5	NM_001317163.2	c.84-1229G>A		intron_variant	Intron 1 of 40		NP_001304092.1
C5	NM_001317164.2	c.66-1229G>A		intron_variant	Intron 1 of 20		NP_001304093.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C5	ENST00000223642.3	c.66-1229G>A		intron_variant	Intron 1 of 40	1	NM_001735.3	ENSP00000223642.1

Frequencies

GnomAD3 genomes AF: 0.514 AC: 78181 AN: 151990 Hom.: 22440 Cov.: 32

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.741

Gnomad AMR AF: 0.674

Gnomad ASJ AF: 0.649

Gnomad EAS AF: 0.742

Gnomad SAS AF: 0.788

Gnomad FIN AF: 0.583

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.580

Gnomad OTH AF: 0.569

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

GnomAD4 genome AF: 0.514 AC: 78229 AN: 152108 Hom.: 22455 Cov.: 32 AF XY: 0.522 AC XY: 38839 AN XY: 74360

African (AFR) AF: 0.250 AC: 10389 AN: 41498

American (AMR) AF: 0.674 AC: 10293 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.649 AC: 2252 AN: 3472

East Asian (EAS) AF: 0.742 AC: 3851 AN: 5188

South Asian (SAS) AF: 0.789 AC: 3799 AN: 4814

European-Finnish (FIN) AF: 0.583 AC: 6156 AN: 10568

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.580 AC: 39424 AN: 67988

Other (OTH) AF: 0.569 AC: 1200 AN: 2108

Alfa AF: 0.585 Hom.: 41621

Bravo AF: 0.511

Asia WGS AF: 0.699 AC: 2429 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	8.0
DANN	Benign	0.67
PhyloP100		0.31
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1468673; hg19: chr9-123809890; COSMIC: COSV56325501;