9-120961333-C-G

Variant names:

• chr9-120961333-C-G
• rs16910233
• NM_001735.3:c.4588+149G>C

Variant summary

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

The NM_001735.3(C5):​c.4588+149G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0205 in 677,916 control chromosomes in the GnomAD database, including 914 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 0.054 (666 hom., cov: 32)
  • Exomes 𝑓: 0.011 (248 hom.)
• Consequence: C5 NM_001735.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0290
• Publications: 1 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 (AFR) allele frequency at 95% confidence interval = 0.173 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C5	NM_001735.3	MANE Select	c.4588+149G>C		intron	N/A	NP_001726.2
	C5	NM_001317163.2		c.4606+149G>C		intron	N/A	NP_001304092.1	A0A8Q3SID6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C5	ENST00000223642.3	TSL:1 MANE Select	c.4588+149G>C		intron	N/A	ENSP00000223642.1	P01031
	C5	ENST00000696281.1		c.4606+149G>C		intron	N/A	ENSP00000512521.1	A0A8Q3SID6
	C5	ENST00000867873.1		c.4505-996G>C		intron	N/A	ENSP00000537932.1

Frequencies

GnomAD3 genomes AF: 0.0544 AC: 8267 AN: 152098 Hom.: 665 Cov.: 32

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0280

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00637

Gnomad OTH AF: 0.0378

GnomAD4 exome AF: 0.0106 AC: 5596 AN: 525700 Hom.: 248 AF XY: 0.00900 AC XY: 2548 AN XY: 283062

African (AFR) AF: 0.173 AC: 2582 AN: 14934

American (AMR) AF: 0.0181 AC: 591 AN: 32572

Ashkenazi Jewish (ASJ) AF: 0.000390 AC: 7 AN: 17936

East Asian (EAS) AF: 0.00 AC: 0 AN: 31172

South Asian (SAS) AF: 0.000420 AC: 24 AN: 57152

European-Finnish (FIN) AF: 0.000139 AC: 5 AN: 36020

Middle Eastern (MID) AF: 0.0113 AC: 44 AN: 3904

European-Non Finnish (NFE) AF: 0.00594 AC: 1800 AN: 302900

Other (OTH) AF: 0.0187 AC: 543 AN: 29110

GnomAD4 genome AF: 0.0544 AC: 8284 AN: 152216 Hom.: 666 Cov.: 32 AF XY: 0.0535 AC XY: 3979 AN XY: 74432

African (AFR) AF: 0.176 AC: 7313 AN: 41504

American (AMR) AF: 0.0280 AC: 428 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10598

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00635 AC: 432 AN: 68016

Other (OTH) AF: 0.0374 AC: 79 AN: 2112

Alfa AF: 0.0342 Hom.: 46

Bravo AF: 0.0615

Asia WGS AF: 0.0140 AC: 51 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.0
DANN	Benign	0.60
PhyloP100		0.029
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: rs16910233; hg19: chr9-123723611;