5-39341267-A-G

Variant names:

• chr5-39341267-A-G
• rs121909593
• NM_001737.5:c.355T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_001737.5(C9):​c.355T>C​(p.Cys119Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C119G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: C9 NM_001737.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.27
• Publications: 5 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-39341267-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 17042.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001737.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C9	NM_001737.5	MANE Select	c.355T>C	p.Cys119Arg	missense	Exon 4 of 11	NP_001728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C9	ENST00000263408.5	TSL:1 MANE Select	c.355T>C	p.Cys119Arg	missense	Exon 4 of 11	ENSP00000263408.4
	C9	ENST00000509186.6	TSL:3	c.283T>C	p.Cys95Arg	missense	Exon 4 of 11	ENSP00000512235.1
	C9	ENST00000695880.1		c.355T>C	p.Cys119Arg	missense	Exon 4 of 10	ENSP00000512236.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		6.3
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.86		Gain of MoRF binding (P = 0.0145)
MVP		0.95
MPC		0.31
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.99
gMVP		0.98
Mutation Taster		=20/80	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121909593; hg19: chr5-39341369;