rs4844573

Variant names:

Variant summary

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

The NM_000715.4(C4BPA):c.899T>C(p.Ile300Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 1,602,050 control chromosomes in the GnomAD database, including 119,930 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.48 ( 19783 hom., cov: 31)

Exomes 𝑓: 0.36 ( 100147 hom. )

Consequence

C4BPA
NM_000715.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.58

Variant links:

Genes affected

C4BPA (HGNC:1325): (complement component 4 binding protein alpha) This gene encodes a member of a superfamily of proteins composed predominantly of tandemly arrayed short consensus repeats of approximately 60 amino acids. Along with a single, unique beta-chain, seven identical alpha-chains encoded by this gene assemble into the predominant isoform of C4b-binding protein, a multimeric protein that controls activation of the complement cascade through the classical pathway. The genes encoding both alpha and beta chains are located adjacent to each other on human chromosome 1 in the regulator of complement activation gene cluster. Two pseudogenes of this gene are also found in the cluster. [provided by RefSeq, Jul 2008]

C4BPA links:

LOC107985251 (HGNC:):

LOC107985251 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=1.0640223E-6).

BP6

Variant 1-207131555-T-C is Benign according to our data. Variant chr1-207131555-T-C is described in ClinVar as [Benign]. Clinvar id is 402445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-207131555-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.754 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C4BPA	NM_000715.4 link	c.899T>C	p.Ile300Thr	missense_variant	Exon 8 of 12	ENST00000367070.8	NP_000706.1	P04003

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C4BPA	ENST00000367070.8 link	c.899T>C	p.Ile300Thr	missense_variant	Exon 8 of 12	1	NM_000715.4	ENSP00000356037.3		P04003

Frequencies

GnomAD3 genomes

AF:

0.476

AC:

72257

AN:

151802

Hom.:

19736

Cov.:

show subpopulations

Gnomad AFR

AF:

0.761

Gnomad AMI

AF:

0.399

Gnomad AMR

AF:

0.432

Gnomad ASJ

AF:

0.306

Gnomad EAS

AF:

0.274

Gnomad SAS

AF:

0.347

Gnomad FIN

AF:

0.463

Gnomad MID

AF:

0.345

Gnomad NFE

AF:

0.350

Gnomad OTH

AF:

0.443

GnomAD3 exomes

AF:

0.392

AC:

97429

AN:

248352

Hom.:

20794

AF XY:

0.381

AC XY:

51110

AN XY:

134148

show subpopulations

Gnomad AFR exome

AF:

0.769

Gnomad AMR exome

AF:

0.428

Gnomad ASJ exome

AF:

0.306

Gnomad EAS exome

AF:

0.291

Gnomad SAS exome

AF:

0.348

Gnomad FIN exome

AF:

0.466

Gnomad NFE exome

AF:

0.350

Gnomad OTH exome

AF:

0.377

GnomAD4 exome

AF:

0.363

AC:

526452

AN:

1450130

Hom.:

100147

Cov.:

AF XY:

0.361

AC XY:

260456

AN XY:

722064

show subpopulations

Gnomad4 AFR exome

AF:

0.777

Gnomad4 AMR exome

AF:

0.427

Gnomad4 ASJ exome

AF:

0.306

Gnomad4 EAS exome

AF:

0.307

Gnomad4 SAS exome

AF:

0.346

Gnomad4 FIN exome

AF:

0.454

Gnomad4 NFE exome

AF:

0.348

Gnomad4 OTH exome

AF:

0.372

GnomAD4 genome

AF:

0.476

AC:

72375

AN:

151920

Hom.:

19783

Cov.:

AF XY:

0.474

AC XY:

35177

AN XY:

74256

show subpopulations

Gnomad4 AFR

AF:

0.761

Gnomad4 AMR

AF:

0.431

Gnomad4 ASJ

AF:

0.306

Gnomad4 EAS

AF:

0.275

Gnomad4 SAS

AF:

0.347

Gnomad4 FIN

AF:

0.463

Gnomad4 NFE

AF:

0.350

Gnomad4 OTH

AF:

0.444

Alfa

AF:

0.378

Hom.:

20313

Bravo

AF:

0.489

TwinsUK

AF:

0.350

AC:

1296

ALSPAC

AF:

0.340

AC:

1311

ESP6500AA

AF:

0.753

AC:

3316

ESP6500EA

AF:

0.347

AC:

2980

ExAC

AF:

0.396

AC:

48051

Asia WGS

AF:

0.336

AC:

1170

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

0.058

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.055

DANN

Benign

0.32

DEOGEN2

Benign

0.016

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0022

LIST_S2

Benign

0.051

MetaRNN

Benign

0.0000011

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.73

PrimateAI

Benign

0.28

PROVEAN

Benign

0.62

REVEL

Benign

0.12

Sift

Benign

0.92

Sift4G

Benign

0.87

Polyphen

0.0

Vest4

0.0080

MPC

0.32

ClinPred

0.0031

GERP RS

-8.9

Varity_R

0.030

gMVP

0.20

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