9-121009521-T-C

Variant names:

• chr9-121009521-T-C
• rs7027797
• NM_001735.3:c.2258-1023A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 17 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=-0.93).
• 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 rank	MANE	Protein	UniProt
C5	NM_001735.3	c.2258-1023A>G		intron_variant	Intron 17 of 40	ENST00000223642.3	NP_001726.2
C5	NM_001317163.2	c.2276-1023A>G		intron_variant	Intron 17 of 40		NP_001304092.1
C5	NM_001317164.2	c.2258-1023A>G		intron_variant	Intron 17 of 20		NP_001304093.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C5	ENST00000223642.3	c.2258-1023A>G		intron_variant	Intron 17 of 40	1	NM_001735.3	ENSP00000223642.1

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

African (AFR) AF: 0.137 AC: 5675 AN: 41538

American (AMR) AF: 0.0760 AC: 1162 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0590 AC: 205 AN: 3472

East Asian (EAS) AF: 0.0322 AC: 167 AN: 5186

South Asian (SAS) AF: 0.0911 AC: 440 AN: 4828

European-Finnish (FIN) AF: 0.0626 AC: 664 AN: 10608

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.109 AC: 7394 AN: 68004

Other (OTH) AF: 0.0814 AC: 172 AN: 2114

Alfa AF: 0.106 Hom.: 1518

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
PhyloP100		-0.86
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: rs7027797; hg19: chr9-123771799;