5-39288783-C-T

Position:

chr5-39288783-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -1.19

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 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: {Likely_benign=1, Uncertain_significance=1}.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C9	NM_001737.5 linkuse as main transcript	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 linkuse as main transcript	c.1585G>A	p.Ala529Thr	missense_variant	10/11	1	NM_001737.5	P2

Frequencies

GnomAD3 genomes

AF:

0.000402

AC:

AN:

151840

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000663

AC XY:

AN XY:

135652

show subpopulations

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.:

Cov.:

AF XY:

0.000734

AC XY:

533

AN XY:

726544

show subpopulations

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:

AN:

151958

Hom.:

Cov.:

AF XY:

0.000485

AC XY:

AN XY:

74258

show subpopulations

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.:

Bravo

AF:

0.000272

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000511

AC:

EpiCase

AF:

0.000546

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

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

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.049

DANN

Benign

0.45

DEOGEN2

Benign

0.0082

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.37

M_CAP

Benign

0.021

MetaRNN

Benign

0.014

MetaSVM

Benign

-0.88

MutationAssessor

Benign

-0.84

MutationTaster

Benign

1.0

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.20

REVEL

Benign

0.23

Sift

Benign

0.81

Sift4G

Benign

0.74

Polyphen

0.0

Vest4

0.040

MVP

0.46

MPC

0.032

ClinPred

0.00073

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

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