chr9-120963648-T-G

Position:

chr9-120963648-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000223642.3(C5):c.4311A>C(p.Glu1437Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.061 in 1,610,638 control chromosomes in the GnomAD database, including 3,483 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.045 ( 230 hom., cov: 32)

Exomes 𝑓: 0.063 ( 3253 hom. )

Consequence

C5
ENST00000223642.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.209

Variant links:

Genes affected

C5 (HGNC:1331): (complement C5) This gene encodes a component of the complement system, a part of the innate immune system that plays an important role in inflammation, host homeostasis, and host defense against pathogens. The encoded preproprotein is proteolytically processed to generate multiple protein products, including the C5 alpha chain, C5 beta chain, C5a anaphylatoxin and C5b. The C5 protein is comprised of the C5 alpha and beta chains, which are linked by a disulfide bridge. Cleavage of the alpha chain by a convertase enzyme results in the formation of the C5a anaphylatoxin, which possesses potent spasmogenic and chemotactic activity, and the C5b macromolecular cleavage product, a subunit of the membrane attack complex (MAC). Mutations in this gene cause complement component 5 deficiency, a disease characterized by recurrent bacterial infections. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2015]

C5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017857254).

BP6

Variant 9-120963648-T-G is Benign according to our data. Variant chr9-120963648-T-G is described in ClinVar as [Benign]. Clinvar id is 402451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0672 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C5	NM_001735.3 linkuse as main transcript	c.4311A>C	p.Glu1437Asp	missense_variant	34/41	ENST00000223642.3	NP_001726.2
C5	NM_001317163.2 linkuse as main transcript	c.4329A>C	p.Glu1443Asp	missense_variant	34/41		NP_001304092.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C5	ENST00000223642.3 linkuse as main transcript	c.4311A>C	p.Glu1437Asp	missense_variant	34/41	1	NM_001735.3	ENSP00000223642	P1

Frequencies

GnomAD3 genomes

AF:

0.0454

AC:

6910

AN:

152210

Hom.:

230

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0188

Gnomad AMI

AF:

0.0307

Gnomad AMR

AF:

0.0547

Gnomad ASJ

AF:

0.0629

Gnomad EAS

AF:

0.00115

Gnomad SAS

AF:

0.0741

Gnomad FIN

AF:

0.0132

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.0649

Gnomad OTH

AF:

0.0478

GnomAD3 exomes

AF:

0.0537

AC:

13490

AN:

251280

Hom.:

474

AF XY:

0.0547

AC XY:

7429

AN XY:

135800

show subpopulations

Gnomad AFR exome

AF:

0.0191

Gnomad AMR exome

AF:

0.0578

Gnomad ASJ exome

AF:

0.0646

Gnomad EAS exome

AF:

0.000870

Gnomad SAS exome

AF:

0.0671

Gnomad FIN exome

AF:

0.0152

Gnomad NFE exome

AF:

0.0685

Gnomad OTH exome

AF:

0.0570

GnomAD4 exome

AF:

0.0626

AC:

91337

AN:

1458310

Hom.:

3253

Cov.:

AF XY:

0.0630

AC XY:

45745

AN XY:

725660

show subpopulations

Gnomad4 AFR exome

AF:

0.0181

Gnomad4 AMR exome

AF:

0.0566

Gnomad4 ASJ exome

AF:

0.0618

Gnomad4 EAS exome

AF:

0.000731

Gnomad4 SAS exome

AF:

0.0673

Gnomad4 FIN exome

AF:

0.0168

Gnomad4 NFE exome

AF:

0.0685

Gnomad4 OTH exome

AF:

0.0597

GnomAD4 genome

AF:

0.0453

AC:

6906

AN:

152328

Hom.:

230

Cov.:

AF XY:

0.0430

AC XY:

3202

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.0189

Gnomad4 AMR

AF:

0.0545

Gnomad4 ASJ

AF:

0.0629

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.0735

Gnomad4 FIN

AF:

0.0132

Gnomad4 NFE

AF:

0.0649

Gnomad4 OTH

AF:

0.0473

Alfa

AF:

0.0644

Hom.:

720

Bravo

AF:

0.0472

TwinsUK

AF:

0.0739

AC:

274

ALSPAC

AF:

0.0667

AC:

257

ESP6500AA

AF:

0.0229

AC:

101

ESP6500EA

AF:

0.0698

AC:

600

ExAC

AF:

0.0549

AC:

6662

Asia WGS

AF:

0.0340

AC:

118

AN:

3478

EpiCase

AF:

0.0701

EpiControl

AF:

0.0711

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.76

CADD

Benign

5.4

DANN

Benign

0.96

DEOGEN2

Benign

0.079

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.52

MetaRNN

Benign

0.0018

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

MutationTaster

Benign

0.76

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.1

REVEL

Benign

0.073

Sift

Benign

0.14

Sift4G

Benign

0.43

Polyphen

0.0020

Vest4

0.062

MutPred

0.26

Loss of ubiquitination at K1440 (P = 0.1741);

MPC

0.16

ClinPred

0.0035

GERP RS

-2.9

Varity_R

0.38

gMVP

0.53

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

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