chr9-121022971-A-G

Variant names:

• chr9-121022971-A-G
• rs993247
• NM_001735.3:c.1116+433T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 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=-0.81).
• 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 rank	MANE	Protein	UniProt
C5	NM_001735.3	c.1116+433T>C		intron_variant	Intron 10 of 40	ENST00000223642.3	NP_001726.2
C5	NM_001317163.2	c.1134+433T>C		intron_variant	Intron 10 of 40		NP_001304092.1
C5	NM_001317164.2	c.1116+433T>C		intron_variant	Intron 10 of 20		NP_001304093.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C5	ENST00000223642.3	c.1116+433T>C		intron_variant	Intron 10 of 40	1	NM_001735.3	ENSP00000223642.1

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

African (AFR) AF: 0.126 AC: 5204 AN: 41418

American (AMR) AF: 0.495 AC: 7545 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.522 AC: 1808 AN: 3466

East Asian (EAS) AF: 0.561 AC: 2902 AN: 5170

South Asian (SAS) AF: 0.637 AC: 3058 AN: 4800

European-Finnish (FIN) AF: 0.511 AC: 5353 AN: 10474

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.436 AC: 29549 AN: 67822

Other (OTH) AF: 0.417 AC: 878 AN: 2106

Alfa AF: 0.434 Hom.: 10201

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
PhyloP100		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs993247; hg19: chr9-123785249;