rs41312901

Positions:

• chr9-120963751-A-G

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.4221-13T>C 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 0.0637 in 1,581,644 control chromosomes in the GnomAD database, including 3,579 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (293 hom., cov: 32)
  • Exomes 𝑓: 0.064 (3286 hom.)
• Consequence: C5 NM_001735.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.48

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=-0.82).
• BP6: Variant 9-120963751-A-G is Benign according to our data. Variant chr9-120963751-A-G is described in ClinVar as [Benign]. Clinvar id is 402452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0671 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C5	NM_001735.3	c.4221-13T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000223642.3
C5	NM_001317163.2	c.4239-13T>C		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C5	ENST00000223642.3	c.4221-13T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001735.3	P1

Frequencies

GnomAD3 genomes AF: 0.0572 AC: 8706 AN: 152200 Hom.: 292 Cov.: 32

Gnomad AFR AF: 0.0600

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0593

Gnomad ASJ AF: 0.0628

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0739

Gnomad FIN AF: 0.0132

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0649

Gnomad OTH AF: 0.0569

GnomAD3 exomes AF: 0.0572 AC: 14151 AN: 247360 Hom.: 494 AF XY: 0.0574 AC XY: 7683 AN XY: 133880

Gnomad AFR exome AF: 0.0627

Gnomad AMR exome AF: 0.0600

Gnomad ASJ exome AF: 0.0650

Gnomad EAS exome AF: 0.000829

Gnomad SAS exome AF: 0.0676

Gnomad FIN exome AF: 0.0153

Gnomad NFE exome AF: 0.0692

Gnomad OTH exome AF: 0.0588

GnomAD4 exome AF: 0.0644 AC: 92028 AN: 1429326 Hom.: 3286 Cov.: 25 AF XY: 0.0645 AC XY: 46015 AN XY: 713010

Gnomad4 AFR exome AF: 0.0631

Gnomad4 AMR exome AF: 0.0590

Gnomad4 ASJ exome AF: 0.0619

Gnomad4 EAS exome AF: 0.000686

Gnomad4 SAS exome AF: 0.0675

Gnomad4 FIN exome AF: 0.0167

Gnomad4 NFE exome AF: 0.0692

Gnomad4 OTH exome AF: 0.0634

GnomAD4 genome AF: 0.0572 AC: 8714 AN: 152318 Hom.: 293 Cov.: 32 AF XY: 0.0551 AC XY: 4104 AN XY: 74476

Gnomad4 AFR AF: 0.0601

Gnomad4 AMR AF: 0.0590

Gnomad4 ASJ AF: 0.0628

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0734

Gnomad4 FIN AF: 0.0132

Gnomad4 NFE AF: 0.0650

Gnomad4 OTH AF: 0.0573

Alfa AF: 0.0627 Hom.: 88

Bravo AF: 0.0608

Asia WGS AF: 0.0400 AC: 141 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	16
DANN	Benign	0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs41312901; hg19: chr9-123726029;