9-121026114-T-C

Variant names:

• chr9-121026114-T-C
• rs7033790
• NM_001735.3:c.874-534A>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.874-534A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.75 in 152,032 control chromosomes in the GnomAD database, including 43,249 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 0.75 (43249 hom., cov: 31)
• Consequence: C5 NM_001735.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.31
• Publications: 4 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=-0.7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.972 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C5	NM_001735.3	c.874-534A>G		intron_variant	Intron 8 of 40	ENST00000223642.3	NP_001726.2
C5	NM_001317163.2	c.892-534A>G		intron_variant	Intron 8 of 40		NP_001304092.1
C5	NM_001317164.2	c.874-534A>G		intron_variant	Intron 8 of 20		NP_001304093.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C5	ENST00000223642.3	c.874-534A>G		intron_variant	Intron 8 of 40	1	NM_001735.3	ENSP00000223642.1

Frequencies

GnomAD3 genomes AF: 0.750 AC: 113983 AN: 151914 Hom.: 43207 Cov.: 31

Gnomad AFR AF: 0.652

Gnomad AMI AF: 0.844

Gnomad AMR AF: 0.814

Gnomad ASJ AF: 0.765

Gnomad EAS AF: 0.995

Gnomad SAS AF: 0.930

Gnomad FIN AF: 0.715

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.767

Gnomad OTH AF: 0.767

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

GnomAD4 genome AF: 0.750 AC: 114083 AN: 152032 Hom.: 43249 Cov.: 31 AF XY: 0.752 AC XY: 55897 AN XY: 74306

African (AFR) AF: 0.653 AC: 27038 AN: 41436

American (AMR) AF: 0.814 AC: 12438 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.765 AC: 2655 AN: 3470

East Asian (EAS) AF: 0.995 AC: 5161 AN: 5188

South Asian (SAS) AF: 0.930 AC: 4475 AN: 4814

European-Finnish (FIN) AF: 0.715 AC: 7525 AN: 10530

Middle Eastern (MID) AF: 0.755 AC: 222 AN: 294

European-Non Finnish (NFE) AF: 0.767 AC: 52180 AN: 68000

Other (OTH) AF: 0.768 AC: 1619 AN: 2108

Alfa AF: 0.745 Hom.: 6066

Bravo AF: 0.754

Asia WGS AF: 0.934 AC: 3242 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	15
DANN	Benign	0.85
PhyloP100		1.3
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: rs7033790; hg19: chr9-123788392;