Variant 5-39342112-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001737.5(C9):c.162C>A(p.Cys54Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,591,052 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. C54C) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00093 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 2 hom. )

Consequence

C9
NM_001737.5 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 0.969

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

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

PP5

Variant 5-39342112-G-T is Pathogenic according to our data. Variant chr5-39342112-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C9	NM_001737.5 linkuse as main transcript	c.162C>A	p.Cys54Ter	stop_gained	2/11	ENST00000263408.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C9	ENST00000263408.5 linkuse as main transcript	c.162C>A	p.Cys54Ter	stop_gained	2/11	1	NM_001737.5	P2

Frequencies

GnomAD3 genomes

AF:

0.000927

AC:

141

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00207

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00135

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000891

AC:

224

AN:

251468

Hom.:

AF XY:

0.000846

AC XY:

115

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00152

Gnomad NFE exome

AF:

0.00147

Gnomad OTH exome

AF:

0.000814

GnomAD4 exome

AF:

0.00122

AC:

1752

AN:

1438790

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

895

AN XY:

717426

show subpopulations

Gnomad4 AFR exome

AF:

0.000212

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.000846

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000233

Gnomad4 FIN exome

AF:

0.00131

Gnomad4 NFE exome

AF:

0.00145

Gnomad4 OTH exome

AF:

0.000872

GnomAD4 genome

AF:

0.000926

AC:

141

AN:

152262

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00207

Gnomad4 NFE

AF:

0.00135

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000936

Hom.:

Bravo

AF:

0.000933

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.000988

AC:

120

EpiCase

AF:

0.00142

EpiControl

AF:

0.00124

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Complement component 9 deficiency

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	research	ITMI	Feb 28, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 28, 2023	The p.Cys54X variant in C9 has been reported in at least 2 compound heterozygous individuals with C9 deficiency and segregated with disease at least 1 affected family member (selected publications: Hobart 1997 PMID: 9182899, Witzel-Schlomp 1997 PMID: 9144525, Witzel-Schlömp 1998 PMID: 9634479). It has been identified in 0.2% (22/10620) of Finnish chromosomes by gnomAD v3.1.2 (https://gnomad.broadinstitute.org/) and has also been reported in ClinVar (Variation ID 17041). This nonsense variant leads to a premature termination codon at position 54, which is predicted to lead to a truncated or absent protein. Loss of function of the C9 gene is an established disease mechanism in autosomal recessive C9 deficiency. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive C9 deficiency. ACMG/AMP criteria applied: PVS1, PM3, PP1 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1998	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 14, 2015	The C54X variant in the C9 gene has been reported previously in association with complement 9 deficiency (Witzel-Schlomp et al., 1997). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The NHLBI ESP Exome Sequencing Project reports C54X was observed at a frequency of 0.24%, 21/8600 alleles from individuals of European ancestry, and at a frequency of 0.11%, 5/4406 alleles from individuals of African American ancestry indicating it may be a rare variant in this population. We interpret C54X as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	This sequence change creates a premature translational stop signal (p.Cys54*) 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 (rs34000044, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with C9-deficiency (PMID: 9144525, 9634479). ClinVar contains an entry for this variant (Variation ID: 17041). For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 07, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.095

FATHMM_MKL

Benign

0.59

MutationTaster

Benign

1.0

Vest4

0.65

GERP RS

2.9

Splicing

Name

Calibrated prediction

Score

Prediction

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

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