chr9-121000398-T-A

Variant names:

• chr9-121000398-T-A
• rs1978270
• NM_001735.3:c.2563-2624A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001735.3(C5):​c.2563-2624A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.576 in 151,998 control chromosomes in the GnomAD database, including 26,003 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 0.58 (26003 hom., cov: 32)
• Consequence: C5 NM_001735.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.338
• 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=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.792 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C5	NM_001735.3	c.2563-2624A>T		intron_variant	Intron 20 of 40	ENST00000223642.3	NP_001726.2
C5	NM_001317163.2	c.2581-2624A>T		intron_variant	Intron 20 of 40		NP_001304092.1
C5	NM_001317164.2	c.2563-347A>T		intron_variant	Intron 20 of 20		NP_001304093.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C5	ENST00000223642.3	c.2563-2624A>T		intron_variant	Intron 20 of 40	1	NM_001735.3	ENSP00000223642.1

Frequencies

GnomAD3 genomes AF: 0.576 AC: 87546 AN: 151880 Hom.: 25979 Cov.: 32

Gnomad AFR AF: 0.430

Gnomad AMI AF: 0.705

Gnomad AMR AF: 0.622

Gnomad ASJ AF: 0.636

Gnomad EAS AF: 0.813

Gnomad SAS AF: 0.756

Gnomad FIN AF: 0.639

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.610

Gnomad OTH AF: 0.584

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

GnomAD4 genome AF: 0.576 AC: 87624 AN: 151998 Hom.: 26003 Cov.: 32 AF XY: 0.580 AC XY: 43103 AN XY: 74298

African (AFR) AF: 0.430 AC: 17831 AN: 41436

American (AMR) AF: 0.622 AC: 9509 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.636 AC: 2206 AN: 3466

East Asian (EAS) AF: 0.813 AC: 4198 AN: 5164

South Asian (SAS) AF: 0.756 AC: 3648 AN: 4828

European-Finnish (FIN) AF: 0.639 AC: 6758 AN: 10570

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.610 AC: 41422 AN: 67938

Other (OTH) AF: 0.587 AC: 1239 AN: 2110

Alfa AF: 0.591 Hom.: 3409

Bravo AF: 0.567

Asia WGS AF: 0.755 AC: 2617 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.0
DANN	Benign	0.44
PhyloP100		-0.34
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: rs1978270; hg19: chr9-123762676;