9-121045942-T-C

Variant names:

• chr9-121045942-T-C
• rs7040603
• NM_001735.3:c.258+249A>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.258+249A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.743 in 152,040 control chromosomes in the GnomAD database, including 42,438 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 0.74 (42438 hom., cov: 32)
• Consequence: C5 NM_001735.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.320
• Publications: 5 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=-0.72).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.937 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C5	NM_001735.3	c.258+249A>G		intron_variant	Intron 2 of 40	ENST00000223642.3	NP_001726.2
C5	NM_001317163.2	c.276+249A>G		intron_variant	Intron 2 of 40		NP_001304092.1
C5	NM_001317164.2	c.258+249A>G		intron_variant	Intron 2 of 20		NP_001304093.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C5	ENST00000223642.3	c.258+249A>G		intron_variant	Intron 2 of 40	1	NM_001735.3	ENSP00000223642.1

Frequencies

GnomAD3 genomes AF: 0.743 AC: 112847 AN: 151922 Hom.: 42397 Cov.: 32

Gnomad AFR AF: 0.631

Gnomad AMI AF: 0.844

Gnomad AMR AF: 0.811

Gnomad ASJ AF: 0.764

Gnomad EAS AF: 0.959

Gnomad SAS AF: 0.927

Gnomad FIN AF: 0.715

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.767

Gnomad OTH AF: 0.758

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

GnomAD4 genome AF: 0.743 AC: 112946 AN: 152040 Hom.: 42438 Cov.: 32 AF XY: 0.744 AC XY: 55324 AN XY: 74334

African (AFR) AF: 0.632 AC: 26217 AN: 41484

American (AMR) AF: 0.811 AC: 12382 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.764 AC: 2648 AN: 3466

East Asian (EAS) AF: 0.959 AC: 4973 AN: 5186

South Asian (SAS) AF: 0.926 AC: 4469 AN: 4824

European-Finnish (FIN) AF: 0.715 AC: 7559 AN: 10576

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

European-Non Finnish (NFE) AF: 0.767 AC: 52111 AN: 67926

Other (OTH) AF: 0.757 AC: 1595 AN: 2106

Alfa AF: 0.707 Hom.: 4205

Bravo AF: 0.745

Asia WGS AF: 0.902 AC: 3102 AN: 3442

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	11
DANN	Benign	0.88
PhyloP100		-0.32
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: rs7040603; hg19: chr9-123808220;