Variant chr1-207089587-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001017365.3(C4BPB):c.56A>G(p.Asp19Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/25 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

C4BPB
NM_001017365.3 missense, splice_region

Scores

Splicing: ADA: 0.0005728

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.524

Variant links:

Genes affected

C4BPB (HGNC:1328): (complement component 4 binding protein beta) This gene encodes a member of a superfamily of proteins composed predominantly of tandemly arrayed short consensus repeats of approximately 60 amino acids. A single, unique beta-chain encoded by this gene assembles with seven identical alpha-chains into the predominant isoform of C4b-binding protein, a multimeric protein that controls activation of the complement cascade through the classical pathway. C4b-binding protein has a regulatory role in the coagulation system also, mediated through the beta-chain binding of protein S, a vitamin K-dependent protein that serves as a cofactor of activated protein C. 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. Alternative splicing gives rise to multiple transcript variants. [provided by RefSeq, Jul 2008]

C4BPB links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07399219).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C4BPB	NM_001017365.3 linkuse as main transcript	c.56A>G	p.Asp19Gly	missense_variant, splice_region_variant	2/7	ENST00000367078.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C4BPB	ENST00000367078.8 linkuse as main transcript	c.56A>G	p.Asp19Gly	missense_variant, splice_region_variant	2/7	1	NM_001017365.3	P4	P20851-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461664

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727168

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2023

The c.56A>G (p.D19G) alteration is located in exon 1 (coding exon 1) of the C4BPB gene. This alteration results from a A to G substitution at nucleotide position 56, causing the aspartic acid (D) at amino acid position 19 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.78

DEOGEN2

Benign

0.093

T;T;T;.;T

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.34

.;T;.;T;T

M_CAP

Benign

0.0029

MetaRNN

Benign

0.074

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

L;.;L;L;L

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.2

N;N;N;N;N

REVEL

Benign

0.0060

Sift

Benign

0.055

T;D;T;T;T

Sift4G

Benign

0.074

T;T;T;T;T

Polyphen

0.0010

B;.;B;B;B

Vest4

0.34

MutPred

0.28

Gain of glycosylation at S18 (P = 0.0351);Gain of glycosylation at S18 (P = 0.0351);Gain of glycosylation at S18 (P = 0.0351);Gain of glycosylation at S18 (P = 0.0351);Gain of glycosylation at S18 (P = 0.0351);

MVP

0.014

MPC

0.20

ClinPred

0.17

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.095

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00057

dbscSNV1_RF

Benign

0.030

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.20

Position offset: -1

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