rs476569

Variant names:

• chr5-39342206-C-T
• rs476569
• NM_001737.5:c.78-10G>A

Variant summary

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

The NM_001737.5(C9):​c.78-10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.522 in 1,412,842 control chromosomes in the GnomAD database, including 195,334 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (28533 hom., cov: 32)
  • Exomes 𝑓: 0.51 (166801 hom.)
• Consequence: C9 NM_001737.5 intron
• Scores: Splicing: ADA: 0.0001237
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.911
• Publications: 12 publications found

Genes affected

C9 (HGNC:1358): (complement C9) This gene encodes the final component of the complement system. It participates in the formation of the Membrane Attack Complex (MAC). The MAC assembles on bacterial membranes to form a pore, permitting disruption of bacterial membrane organization. Mutations in this gene cause component C9 deficiency. [provided by RefSeq, Feb 2009]

C9 Gene-Disease associations (from GenCC):

• complement component 9 deficiency

  Inheritance: Unknown, AR Classification: STRONG, MODERATE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000289699 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BP6: Variant 5-39342206-C-T is Benign according to our data. Variant chr5-39342206-C-T is described in ClinVar as Benign. ClinVar VariationId is 402465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.811 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C9	NM_001737.5	c.78-10G>A		intron_variant	Intron 1 of 10	ENST00000263408.5	NP_001728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C9	ENST00000263408.5	c.78-10G>A		intron_variant	Intron 1 of 10	1	NM_001737.5	ENSP00000263408.4

Frequencies

GnomAD3 genomes AF: 0.595 AC: 90348 AN: 151956 Hom.: 28480 Cov.: 32

Gnomad AFR AF: 0.818

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.635

Gnomad ASJ AF: 0.598

Gnomad EAS AF: 0.507

Gnomad SAS AF: 0.516

Gnomad FIN AF: 0.406

Gnomad MID AF: 0.640

Gnomad NFE AF: 0.492

Gnomad OTH AF: 0.618

GnomAD2 exomes AF: 0.533 AC: 133758 AN: 250884 AF XY: 0.526

Gnomad AFR exome AF: 0.829

Gnomad AMR exome AF: 0.620

Gnomad ASJ exome AF: 0.597

Gnomad EAS exome AF: 0.505

Gnomad FIN exome AF: 0.399

Gnomad NFE exome AF: 0.493

Gnomad OTH exome AF: 0.542

GnomAD4 exome AF: 0.513 AC: 647207 AN: 1260768 Hom.: 166801 Cov.: 19 AF XY: 0.512 AC XY: 326488 AN XY: 637618

African (AFR) AF: 0.836 AC: 25062 AN: 29980

American (AMR) AF: 0.625 AC: 27803 AN: 44478

Ashkenazi Jewish (ASJ) AF: 0.596 AC: 14884 AN: 24970

East Asian (EAS) AF: 0.531 AC: 20609 AN: 38826

South Asian (SAS) AF: 0.513 AC: 42176 AN: 82272

European-Finnish (FIN) AF: 0.398 AC: 21235 AN: 53308

Middle Eastern (MID) AF: 0.604 AC: 3244 AN: 5370

European-Non Finnish (NFE) AF: 0.500 AC: 463505 AN: 927756

Other (OTH) AF: 0.533 AC: 28689 AN: 53808

GnomAD4 genome AF: 0.595 AC: 90462 AN: 152074 Hom.: 28533 Cov.: 32 AF XY: 0.591 AC XY: 43923 AN XY: 74320

African (AFR) AF: 0.818 AC: 33966 AN: 41502

American (AMR) AF: 0.635 AC: 9694 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.598 AC: 2075 AN: 3470

East Asian (EAS) AF: 0.507 AC: 2611 AN: 5150

South Asian (SAS) AF: 0.517 AC: 2488 AN: 4816

European-Finnish (FIN) AF: 0.406 AC: 4296 AN: 10576

Middle Eastern (MID) AF: 0.644 AC: 188 AN: 292

European-Non Finnish (NFE) AF: 0.492 AC: 33433 AN: 67964

Other (OTH) AF: 0.622 AC: 1315 AN: 2114

Alfa AF: 0.547 Hom.: 39848

Bravo AF: 0.623

Asia WGS AF: 0.580 AC: 2022 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 05, 2022

GeneDx

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.0070
DANN	Benign	0.21
PhyloP100		-0.91
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.056
SpliceAI score (max)		0.050		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: rs476569; hg19: chr5-39342308; COSMIC: COSV54677015;