rs41312901

Variant names:

• chr9-120963751-A-G
• rs41312901
• NM_001735.3:c.4221-13T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001735.3(C5):​c.4221-13T>C variant causes a 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 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.48
• Publications: 6 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 -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 VariationId 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 rank	MANE	Protein	UniProt
C5	NM_001735.3	c.4221-13T>C		intron_variant	Intron 33 of 40	ENST00000223642.3	NP_001726.2
C5	NM_001317163.2	c.4239-13T>C		intron_variant	Intron 33 of 40		NP_001304092.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C5	ENST00000223642.3	c.4221-13T>C		intron_variant	Intron 33 of 40	1	NM_001735.3	ENSP00000223642.1

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

GnomAD2 exomes AF: 0.0572 AC: 14151 AN: 247360 AF XY: 0.0574

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 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

African (AFR) AF: 0.0631 AC: 2050 AN: 32500

American (AMR) AF: 0.0590 AC: 2631 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.0619 AC: 1601 AN: 25876

East Asian (EAS) AF: 0.000686 AC: 27 AN: 39378

South Asian (SAS) AF: 0.0675 AC: 5758 AN: 85286

European-Finnish (FIN) AF: 0.0167 AC: 892 AN: 53258

Middle Eastern (MID) AF: 0.0628 AC: 359 AN: 5720

European-Non Finnish (NFE) AF: 0.0692 AC: 74955 AN: 1083454

Other (OTH) AF: 0.0634 AC: 3755 AN: 59256

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

African (AFR) AF: 0.0601 AC: 2498 AN: 41548

American (AMR) AF: 0.0590 AC: 903 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0628 AC: 218 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5190

South Asian (SAS) AF: 0.0734 AC: 354 AN: 4826

European-Finnish (FIN) AF: 0.0132 AC: 140 AN: 10624

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0650 AC: 4419 AN: 68036

Other (OTH) AF: 0.0573 AC: 121 AN: 2112

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.82
CADD	Benign	16
DANN	Benign	0.61
PhyloP100		1.5
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: rs41312901; hg19: chr9-123726029;