5-39341276-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 16P and 1B. PVS1PP5_Very_StrongBS1_Supporting

The NM_001737.5(C9):c.346C>T(p.Arg116*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000649 in 1,613,954 control chromosomes in the GnomAD database, including 15 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00057 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00066 ( 14 hom. )

Consequence

C9
NM_001737.5 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 0.0690

Variant links:

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 links:

ENSG00000289699 (HGNC:):

ENSG00000289699 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 5-39341276-G-A is Pathogenic according to our data. Variant chr5-39341276-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-39341276-G-A is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000658 (962/1461760) while in subpopulation EAS AF= 0.0218 (865/39700). AF 95% confidence interval is 0.0206. There are 14 homozygotes in gnomad4_exome. There are 464 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C9	NM_001737.5 link	c.346C>T	p.Arg116*	stop_gained	Exon 4 of 11	ENST00000263408.5	NP_001728.1	P02748

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C9	ENST00000263408.5 link	c.346C>T	p.Arg116*	stop_gained	Exon 4 of 11	1	NM_001737.5	ENSP00000263408.4		P02748

Frequencies

GnomAD3 genomes

AF:

0.000572

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0153

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000868

AC:

218

AN:

251092

Hom.:

AF XY:

0.000803

AC XY:

109

AN XY:

135748

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0107

Gnomad SAS exome

AF:

0.000425

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000658

AC:

962

AN:

1461760

Hom.:

Cov.:

AF XY:

0.000638

AC XY:

464

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0218

Gnomad4 SAS exome

AF:

0.000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.000695

GnomAD4 genome

AF:

0.000565

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000645

AC XY:

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0151

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000355

Hom.:

Bravo

AF:

0.000344

ExAC

AF:

0.000824

AC:

100

Asia WGS

AF:

0.00751

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Complement component 9 deficiency

Pathogenic:5

Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_001737.3:c.346C>T in the C9 gene has an allele frequency of 0.01 in East Asian subpopulation in the gnomAD database. The C9 c.346C>T (p.Arg116*) variant has been reported in five Japanese C9-deficient patients in homozygous states (PMID: 9703418; 11359403). Another study revealed that eight of the 10 C9D subjects were homozygous for this variant, which was assumed to be a founder mutation in Japanese (PMID: 9570574). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1; PM3; PS4. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 26, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 09, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with C9 deficiency (MIM#613825). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0305 - Variant is present in gnomAD >=0.01 and <0.03 for a recessive condition (v2: 224 heterozygotes, 0 homozygotes; v3: 87 heterozygotes, 1 homozygote). (I) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in multiple individuals with C9 deficiency and is regarded as a Japanese founder variant (ClinVar, PMID: 9570574). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PVS1+PM3 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2003	- -

Complement component 9 deficiency;C3810042:Age related macular degeneration 15

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 02, 2024

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 23, 2025

This sequence change creates a premature translational stop signal (p.Arg116*) in the C9 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in C9 are known to be pathogenic (PMID: 9144525, 9570574). This variant is present in population databases (rs121909592, gnomAD 1.0%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with complement component 9 (C9) deficiency (PMID: 9570574, 9703418, 12596049, 22190594). It is commonly reported in individuals of East Asian ancestry (PMID: 9570574, 9703418, 12596049, 22190594). This variant is also known as Arg95*. ClinVar contains an entry for this variant (Variation ID: 17040). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.038

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Benign

-0.038

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.065

Vest4

0.90

GERP RS

2.1

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over