9-120969130-G-A

Position:

• chr9-120969130-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001735.3(C5):​c.4163-12C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0936 in 1,610,404 control chromosomes in the GnomAD database, including 13,325 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (4888 hom., cov: 32)
  • Exomes 𝑓: 0.085 (8437 hom.)
• Consequence: C5 NM_001735.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.000006167
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.137

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 9-120969130-G-A is Benign according to our data. Variant chr9-120969130-G-A is described in ClinVar as [Benign]. Clinvar id is 402453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C5	NM_001735.3	c.4163-12C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000223642.3	NP_001726.2
C5	NM_001317163.2	c.4181-12C>T		splice_polypyrimidine_tract_variant, intron_variant			NP_001304092.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C5	ENST00000223642.3	c.4163-12C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001735.3	ENSP00000223642	P1

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27330 AN: 152048 Hom.: 4861 Cov.: 32

Gnomad AFR AF: 0.462

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.0654

Gnomad EAS AF: 0.0395

Gnomad SAS AF: 0.0888

Gnomad FIN AF: 0.0134

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.0752

Gnomad OTH AF: 0.142

GnomAD3 exomes AF: 0.0977 AC: 24539 AN: 251100 Hom.: 2606 AF XY: 0.0905 AC XY: 12289 AN XY: 135718

Gnomad AFR exome AF: 0.478

Gnomad AMR exome AF: 0.0907

Gnomad ASJ exome AF: 0.0662

Gnomad EAS exome AF: 0.0446

Gnomad SAS exome AF: 0.0811

Gnomad FIN exome AF: 0.0157

Gnomad NFE exome AF: 0.0779

Gnomad OTH exome AF: 0.0821

GnomAD4 exome AF: 0.0846 AC: 123347 AN: 1458238 Hom.: 8437 Cov.: 29 AF XY: 0.0833 AC XY: 60417 AN XY: 725608

Gnomad4 AFR exome AF: 0.474

Gnomad4 AMR exome AF: 0.0926

Gnomad4 ASJ exome AF: 0.0648

Gnomad4 EAS exome AF: 0.0281

Gnomad4 SAS exome AF: 0.0818

Gnomad4 FIN exome AF: 0.0174

Gnomad4 NFE exome AF: 0.0777

Gnomad4 OTH exome AF: 0.0996

GnomAD4 genome AF: 0.180 AC: 27405 AN: 152166 Hom.: 4888 Cov.: 32 AF XY: 0.174 AC XY: 12947 AN XY: 74408

Gnomad4 AFR AF: 0.463

Gnomad4 AMR AF: 0.112

Gnomad4 ASJ AF: 0.0654

Gnomad4 EAS AF: 0.0396

Gnomad4 SAS AF: 0.0876

Gnomad4 FIN AF: 0.0134

Gnomad4 NFE AF: 0.0752

Gnomad4 OTH AF: 0.142

Alfa AF: 0.0918 Hom.: 2086

Bravo AF: 0.199

Asia WGS AF: 0.104 AC: 363 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.1
DANN	Benign	0.24

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000062
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs10985112; hg19: chr9-123731408;