5-39288783-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001737.5(C9):c.1585G>A(p.Ala529Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000687 in 1,612,478 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A529A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00040 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (3 hom.)
• Consequence: C9 NM_001737.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.19

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013572186).
• BP6: Variant 5-39288783-C-T is Benign according to our data. Variant chr5-39288783-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1581502.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C9	NM_001737.5	c.1585G>A	p.Ala529Thr	missense_variant	10/11	ENST00000263408.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C9	ENST00000263408.5	c.1585G>A	p.Ala529Thr	missense_variant	10/11	1	NM_001737.5	P2

Frequencies

GnomAD3 genomes AF: 0.000402 AC: 61 AN: 151840 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000619

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000590 AC: 148 AN: 250986 Hom.: 0 AF XY: 0.000663 AC XY: 90 AN XY: 135652

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00219

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000591

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000717 AC: 1047 AN: 1460520 Hom.: 3 Cov.: 30 AF XY: 0.000734 AC XY: 533 AN XY: 726544

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00285

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000659

Gnomad4 OTH exome AF: 0.000879

GnomAD4 genome AF: 0.000401 AC: 61 AN: 151958 Hom.: 2 Cov.: 32 AF XY: 0.000485 AC XY: 36 AN XY: 74258

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000619

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000655 Hom.: 0

Bravo AF: 0.000272

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000511 AC: 62

EpiCase AF: 0.000546

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Complement component 9 deficiency;C3810042:Age related macular degeneration 15 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

C9 NM_001737.4 exon 10 p.Ala529Thr (c.1585G>A): This variant has not been reported in the literature but is present in 0.2% (67/30598) of South Asian alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/5-39288885-C-T). This variant amino acid Threonine (Thr) is present in 15 species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	0.049
Dann	Benign	0.45
DEOGEN2	Benign	0.0082	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-0.84	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.23
Sift	Benign	0.81	T
Sift4G	Benign	0.74	T
Polyphen		0.0	B
Vest4		0.040
MVP		0.46
MPC		0.032
ClinPred		0.00073	T
GERP RS		-8.5
Varity_R		0.084
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs137891079; hg19: chr5-39288885;