chr9-120984518-T-C

Variant names:

• chr9-120984518-T-C
• rs10514838
• NM_001735.3:c.3231-1704A>G

Variant summary

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

The NM_001735.3(C5):​c.3231-1704A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0957 in 152,160 control chromosomes in the GnomAD database, including 773 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 0.096 (773 hom., cov: 31)
• Consequence: C5 NM_001735.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.237
• 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.137 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.3231-1704A>G		intron	N/A	NP_001726.2
	C5	NM_001317163.2		c.3249-1704A>G		intron	N/A	NP_001304092.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C5	ENST00000223642.3	TSL:1 MANE Select	c.3231-1704A>G		intron	N/A	ENSP00000223642.1
	C5	ENST00000696281.1		c.3249-1704A>G		intron	N/A	ENSP00000512521.1
	C5	ENST00000480188.2	TSL:2	n.142-1704A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0957 AC: 14556 AN: 152042 Hom.: 772 Cov.: 31

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0716

Gnomad ASJ AF: 0.0582

Gnomad EAS AF: 0.0314

Gnomad SAS AF: 0.0867

Gnomad FIN AF: 0.0457

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0911

Gnomad OTH AF: 0.0727

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

GnomAD4 genome AF: 0.0957 AC: 14563 AN: 152160 Hom.: 773 Cov.: 31 AF XY: 0.0924 AC XY: 6872 AN XY: 74400

African (AFR) AF: 0.140 AC: 5800 AN: 41462

American (AMR) AF: 0.0714 AC: 1090 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0582 AC: 202 AN: 3470

East Asian (EAS) AF: 0.0311 AC: 161 AN: 5182

South Asian (SAS) AF: 0.0866 AC: 418 AN: 4826

European-Finnish (FIN) AF: 0.0457 AC: 485 AN: 10614

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0911 AC: 6197 AN: 68016

Other (OTH) AF: 0.0729 AC: 154 AN: 2112

Alfa AF: 0.0915 Hom.: 91

Bravo AF: 0.0991

Asia WGS AF: 0.0610 AC: 214 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.1
DANN	Benign	0.30
PhyloP100		-0.24
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs10514838; hg19: chr9-123746796;