9-121045942-T-C

Position:

• chr9-121045942-T-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
C5	NM_001735.3	c.258+249A>G		intron_variant		ENST00000223642.3	NP_001726.2
C5	NM_001317163.2	c.276+249A>G		intron_variant			NP_001304092.1
C5	NM_001317164.2	c.258+249A>G		intron_variant			NP_001304093.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C5	ENST00000223642.3	c.258+249A>G		intron_variant		1	NM_001735.3	ENSP00000223642	P1

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

Gnomad4 AFR AF: 0.632

Gnomad4 AMR AF: 0.811

Gnomad4 ASJ AF: 0.764

Gnomad4 EAS AF: 0.959

Gnomad4 SAS AF: 0.926

Gnomad4 FIN AF: 0.715

Gnomad4 NFE AF: 0.767

Gnomad4 OTH AF: 0.757

Alfa AF: 0.710 Hom.: 4046

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs7040603; hg19: chr9-123808220;