chr9-120994909-A-C

Variant names:

• chr9-120994909-A-C
• rs10818495
• NM_001735.3:c.2851+1331T>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.2851+1331T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.475 in 149,442 control chromosomes in the GnomAD database, including 18,193 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 0.48 (18193 hom., cov: 26)
• Consequence: C5 NM_001735.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.690
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.696 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.2851+1331T>G		intron	N/A	NP_001726.2
	C5	NM_001317163.2		c.2869+1331T>G		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.2851+1331T>G		intron	N/A	ENSP00000223642.1	P01031
	C5	ENST00000696281.1		c.2869+1331T>G		intron	N/A	ENSP00000512521.1	A0A8Q3SID6
	C5	ENST00000867873.1		c.2851+1331T>G		intron	N/A	ENSP00000537932.1

Frequencies

GnomAD3 genomes AF: 0.475 AC: 71000 AN: 149344 Hom.: 18187 Cov.: 26

Gnomad AFR AF: 0.271

Gnomad AMI AF: 0.678

Gnomad AMR AF: 0.568

Gnomad ASJ AF: 0.571

Gnomad EAS AF: 0.590

Gnomad SAS AF: 0.715

Gnomad FIN AF: 0.563

Gnomad MID AF: 0.561

Gnomad NFE AF: 0.532

Gnomad OTH AF: 0.498

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

GnomAD4 genome AF: 0.475 AC: 71016 AN: 149442 Hom.: 18193 Cov.: 26 AF XY: 0.482 AC XY: 35053 AN XY: 72712

African (AFR) AF: 0.270 AC: 11043 AN: 40836

American (AMR) AF: 0.568 AC: 8536 AN: 15030

Ashkenazi Jewish (ASJ) AF: 0.571 AC: 1975 AN: 3460

East Asian (EAS) AF: 0.591 AC: 3010 AN: 5096

South Asian (SAS) AF: 0.716 AC: 3357 AN: 4690

European-Finnish (FIN) AF: 0.563 AC: 5364 AN: 9532

Middle Eastern (MID) AF: 0.562 AC: 163 AN: 290

European-Non Finnish (NFE) AF: 0.532 AC: 35919 AN: 67528

Other (OTH) AF: 0.499 AC: 1033 AN: 2072

Alfa AF: 0.520 Hom.: 17270

Bravo AF: 0.467

Asia WGS AF: 0.592 AC: 2058 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	8.7
DANN	Benign	0.59
PhyloP100		0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs10818495;

hg19: chr9-123757187;

COSMIC: COSV56324257;

COSMIC: COSV56324257;