NM_001735.3:c.65+743G>A

Variant names:

• chr9-121049439-C-T
• rs2300939
• NM_001735.3:c.65+743G>A

Variant summary

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

The NM_001735.3(C5):​c.65+743G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 152,060 control chromosomes in the GnomAD database, including 1,559 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 0.12 (1559 hom., cov: 32)
• Consequence: C5 NM_001735.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.93
• Publications: 7 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 = 0.232 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C5	NM_001735.3	c.65+743G>A		intron_variant	Intron 1 of 40	ENST00000223642.3	NP_001726.2
C5	NM_001317163.2	c.84-3056G>A		intron_variant	Intron 1 of 40		NP_001304092.1
C5	NM_001317164.2	c.65+743G>A		intron_variant	Intron 1 of 20		NP_001304093.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C5	ENST00000223642.3	c.65+743G>A		intron_variant	Intron 1 of 40	1	NM_001735.3	ENSP00000223642.1

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18100 AN: 151942 Hom.: 1554 Cov.: 32

Gnomad AFR AF: 0.236

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0579

Gnomad ASJ AF: 0.0552

Gnomad EAS AF: 0.185

Gnomad SAS AF: 0.0348

Gnomad FIN AF: 0.0695

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0759

Gnomad OTH AF: 0.104

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

GnomAD4 genome AF: 0.119 AC: 18133 AN: 152060 Hom.: 1559 Cov.: 32 AF XY: 0.115 AC XY: 8545 AN XY: 74326

African (AFR) AF: 0.236 AC: 9798 AN: 41472

American (AMR) AF: 0.0578 AC: 882 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0552 AC: 191 AN: 3462

East Asian (EAS) AF: 0.185 AC: 957 AN: 5176

South Asian (SAS) AF: 0.0334 AC: 161 AN: 4822

European-Finnish (FIN) AF: 0.0695 AC: 735 AN: 10576

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0759 AC: 5158 AN: 67970

Other (OTH) AF: 0.104 AC: 219 AN: 2110

Alfa AF: 0.0858 Hom.: 474

Bravo AF: 0.123

Asia WGS AF: 0.130 AC: 450 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	0.40
DANN	Benign	0.59
PhyloP100		-1.9
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: rs2300939; hg19: chr9-123811717;