1-207096510-C-T

Position:

• chr1-207096510-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001017365.3(C4BPB):​c.410-12C>T 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 0.00276 in 1,533,108 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (37 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (46 hom.)
• Consequence: C4BPB NM_001017365.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001969
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.909

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=-0.88).
• BP6: Variant 1-207096510-C-T is Benign according to our data. Variant chr1-207096510-C-T is described in ClinVar as [Benign]. Clinvar id is 402447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0127 (1941/152248) while in subpopulation AFR AF= 0.0424 (1759/41510). AF 95% confidence interval is 0.0407. There are 37 homozygotes in gnomad4. There are 886 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 37 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C4BPB	NM_001017365.3	c.410-12C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000367078.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C4BPB	ENST00000367078.8	c.410-12C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001017365.3	P4

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1937 AN: 152130 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.0424

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00557

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00378 AC: 949 AN: 251026 Hom.: 13 AF XY: 0.00300 AC XY: 407 AN XY: 135662

Gnomad AFR exome AF: 0.0418

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.00974

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000850

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000581

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00166 AC: 2291 AN: 1380860 Hom.: 46 Cov.: 23 AF XY: 0.00157 AC XY: 1086 AN XY: 691990

Gnomad4 AFR exome AF: 0.0437

Gnomad4 AMR exome AF: 0.00240

Gnomad4 ASJ exome AF: 0.00937

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000770

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000315

Gnomad4 OTH exome AF: 0.00350

GnomAD4 genome AF: 0.0127 AC: 1941 AN: 152248 Hom.: 37 Cov.: 32 AF XY: 0.0119 AC XY: 886 AN XY: 74460

Gnomad4 AFR AF: 0.0424

Gnomad4 AMR AF: 0.00556

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0119 Hom.: 5

Bravo AF: 0.0140

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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, no change to splice consensus -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.89
DANN	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000020
dbscSNV1_RF	Benign	0.0020
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

Other links and lift over

dbSNP: rs56054349; hg19: chr1-207269855;