chr1-207096513-T-C

Position:

• chr1-207096513-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001017365.3(C4BPB):​c.410-9T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0785 in 1,554,250 control chromosomes in the GnomAD database, including 5,925 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (965 hom., cov: 32)
  • Exomes 𝑓: 0.076 (4960 hom.)
• Consequence: C4BPB NM_001017365.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00005132
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.124

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-207096513-T-C is Benign according to our data. Variant chr1-207096513-T-C is described in ClinVar as [Benign]. Clinvar id is 402448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C4BPB	NM_001017365.3	c.410-9T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000367078.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C4BPB	ENST00000367078.8	c.410-9T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001017365.3	P4

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15556 AN: 152052 Hom.: 965 Cov.: 32

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.0789

Gnomad AMR AF: 0.0775

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.164

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.0557

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.0705

Gnomad OTH AF: 0.121

GnomAD3 exomes AF: 0.0912 AC: 22869 AN: 250852 Hom.: 1259 AF XY: 0.0928 AC XY: 12580 AN XY: 135566

Gnomad AFR exome AF: 0.164

Gnomad AMR exome AF: 0.0518

Gnomad ASJ exome AF: 0.116

Gnomad EAS exome AF: 0.160

Gnomad SAS exome AF: 0.124

Gnomad FIN exome AF: 0.0564

Gnomad NFE exome AF: 0.0768

Gnomad OTH exome AF: 0.0985

GnomAD4 exome AF: 0.0760 AC: 106513 AN: 1402080 Hom.: 4960 Cov.: 25 AF XY: 0.0778 AC XY: 54586 AN XY: 701354

Gnomad4 AFR exome AF: 0.165

Gnomad4 AMR exome AF: 0.0543

Gnomad4 ASJ exome AF: 0.113

Gnomad4 EAS exome AF: 0.176

Gnomad4 SAS exome AF: 0.119

Gnomad4 FIN exome AF: 0.0553

Gnomad4 NFE exome AF: 0.0659

Gnomad4 OTH exome AF: 0.0911

GnomAD4 genome AF: 0.102 AC: 15564 AN: 152170 Hom.: 965 Cov.: 32 AF XY: 0.101 AC XY: 7521 AN XY: 74408

Gnomad4 AFR AF: 0.163

Gnomad4 AMR AF: 0.0775

Gnomad4 ASJ AF: 0.121

Gnomad4 EAS AF: 0.165

Gnomad4 SAS AF: 0.124

Gnomad4 FIN AF: 0.0557

Gnomad4 NFE AF: 0.0705

Gnomad4 OTH AF: 0.119

Alfa AF: 0.0821 Hom.: 1283

Bravo AF: 0.106

Asia WGS AF: 0.151 AC: 524 AN: 3478

EpiCase AF: 0.0808

EpiControl AF: 0.0824

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

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	GeneDx	Jun 09, 2021	- -

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
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.5
DANN	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000051
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		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: rs3813948; hg19: chr1-207269858;