rs34882957

chr5-39331792-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PS1_Moderate BP4_Strong BP6_Very_Strong BS2

The NM_001737.5(C9):c.499C>T(p.Pro167Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00769 in 1,612,936 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0059 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0079 (62 hom.)
• Consequence: C9 NM_001737.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 3.28

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PS1: Transcript NM_001737.5 (C9) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• BP4: Computational evidence support a benign effect (MetaRNN=0.009836942).
• BP6: Variant 5-39331792-G-A is Benign according to our data. Variant chr5-39331792-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 92120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C9	NM_001737.5	c.499C>T	p.Pro167Ser	missense_variant	5/11	ENST00000263408.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C9	ENST00000263408.5	c.499C>T	p.Pro167Ser	missense_variant	5/11	1	NM_001737.5	P2

Frequencies

GnomAD3 genomes AF: 0.00595 AC: 905 AN: 152136 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00224

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00510

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00982

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.00519 AC: 1306 AN: 251480 Hom.: 5 AF XY: 0.00523 AC XY: 711 AN XY: 135910

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00535

Gnomad ASJ exome AF: 0.00327

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.00356

Gnomad NFE exome AF: 0.00805

Gnomad OTH exome AF: 0.00684

GnomAD4 exome AF: 0.00787 AC: 11499 AN: 1460682 Hom.: 62 Cov.: 30 AF XY: 0.00767 AC XY: 5573 AN XY: 726718

Gnomad4 AFR exome AF: 0.00173

Gnomad4 AMR exome AF: 0.00546

Gnomad4 ASJ exome AF: 0.00291

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000962

Gnomad4 FIN exome AF: 0.00335

Gnomad4 NFE exome AF: 0.00948

Gnomad4 OTH exome AF: 0.00550

GnomAD4 genome AF: 0.00594 AC: 905 AN: 152254 Hom.: 4 Cov.: 32 AF XY: 0.00551 AC XY: 410 AN XY: 74446

Gnomad4 AFR AF: 0.00224

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00510

Gnomad4 NFE AF: 0.00982

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.00881 Hom.: 19

Bravo AF: 0.00548

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00767 AC: 66

ExAC AF: 0.00471 AC: 572

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00851

EpiControl AF: 0.00806

ClinVar

Significance: Likely benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	C9: BS2; ENSG00000289699: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Age related macular degeneration 15 Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Nov 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.0098	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.50
MVP		0.72
MPC		0.25
ClinPred		0.024	T
GERP RS		3.8
Varity_R		0.89
gMVP		0.84

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

Other links and lift over

dbSNP: rs34882957; hg19: chr5-39331894;