NM_001735.3:c.759-82G>A

Variant names:

• chr9-121027356-C-T
• rs2416811
• NM_001735.3:c.759-82G>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.759-82G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.451 in 780,274 control chromosomes in the GnomAD database, including 84,505 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 0.38 (12725 hom., cov: 32)
  • Exomes 𝑓: 0.47 (71780 hom.)
• Consequence: C5 NM_001735.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.131
• Publications: 17 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=-0.83).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.612 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001735.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C5	NM_001735.3	MANE Select	c.759-82G>A		intron	N/A	NP_001726.2
	C5	NM_001317163.2		c.777-82G>A		intron	N/A	NP_001304092.1
	C5	NM_001317164.2		c.759-82G>A		intron	N/A	NP_001304093.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C5	ENST00000223642.3	TSL:1 MANE Select	c.759-82G>A		intron	N/A	ENSP00000223642.1
	C5	ENST00000696281.1		c.777-82G>A		intron	N/A	ENSP00000512521.1
	C5	ENST00000460578.1	TSL:5	n.199-82G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.377 AC: 57211 AN: 151932 Hom.: 12711 Cov.: 32

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.643

Gnomad AMR AF: 0.494

Gnomad ASJ AF: 0.521

Gnomad EAS AF: 0.561

Gnomad SAS AF: 0.629

Gnomad FIN AF: 0.510

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.435

Gnomad OTH AF: 0.415

GnomAD4 exome AF: 0.469 AC: 294599 AN: 628220 Hom.: 71780 AF XY: 0.479 AC XY: 160932 AN XY: 335858

African (AFR) AF: 0.129 AC: 2182 AN: 16934

American (AMR) AF: 0.542 AC: 18596 AN: 34286

Ashkenazi Jewish (ASJ) AF: 0.512 AC: 10481 AN: 20452

East Asian (EAS) AF: 0.529 AC: 17104 AN: 32356

South Asian (SAS) AF: 0.635 AC: 40568 AN: 63888

European-Finnish (FIN) AF: 0.484 AC: 18593 AN: 38398

Middle Eastern (MID) AF: 0.495 AC: 1270 AN: 2564

European-Non Finnish (NFE) AF: 0.442 AC: 171085 AN: 386664

Other (OTH) AF: 0.450 AC: 14720 AN: 32678

GnomAD4 genome AF: 0.376 AC: 57238 AN: 152054 Hom.: 12725 Cov.: 32 AF XY: 0.387 AC XY: 28733 AN XY: 74330

African (AFR) AF: 0.129 AC: 5368 AN: 41494

American (AMR) AF: 0.495 AC: 7565 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.521 AC: 1807 AN: 3468

East Asian (EAS) AF: 0.561 AC: 2901 AN: 5168

South Asian (SAS) AF: 0.630 AC: 3041 AN: 4824

European-Finnish (FIN) AF: 0.510 AC: 5371 AN: 10540

Middle Eastern (MID) AF: 0.476 AC: 139 AN: 292

European-Non Finnish (NFE) AF: 0.435 AC: 29581 AN: 67966

Other (OTH) AF: 0.416 AC: 880 AN: 2114

Alfa AF: 0.339 Hom.: 1882

Bravo AF: 0.364

Asia WGS AF: 0.532 AC: 1849 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.7
DANN	Benign	0.67
PhyloP100		0.13
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: rs2416811; hg19: chr9-123789634; COSMIC: COSV56325480;