1-207090484-A-G

Variant names:

• chr1-207090484-A-G
• rs6690037
• NM_001017365.3:c.232+3A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001017365.3(C4BPB):​c.232+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.491 in 1,597,846 control chromosomes in the GnomAD database, including 201,497 homozygotes. In-silico tool predicts 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (14676 hom., cov: 32)
  • Exomes 𝑓: 0.50 (186821 hom.)
• Consequence: C4BPB NM_001017365.3 splice_region, intron
• Scores: Splicing: ADA: 0.0008636
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.506
• Publications: 19 publications found

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 1-207090484-A-G is Benign according to our data. Variant chr1-207090484-A-G is described in ClinVar as Benign. ClinVar VariationId is 402446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.739 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001017365.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C4BPB	NM_001017365.3	MANE Select	c.232+3A>G		splice_region intron	N/A	NP_001017365.1
	C4BPB	NM_000716.3		c.232+3A>G		splice_region intron	N/A	NP_000707.1
	C4BPB	NM_001017367.1		c.232+3A>G		splice_region intron	N/A	NP_001017367.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C4BPB	ENST00000367078.8	TSL:1 MANE Select	c.232+3A>G		splice_region intron	N/A	ENSP00000356045.3
	C4BPB	ENST00000243611.9	TSL:1	c.232+3A>G		splice_region intron	N/A	ENSP00000243611.5
	C4BPB	ENST00000367076.7	TSL:1	c.229+3A>G		splice_region intron	N/A	ENSP00000356043.3

Frequencies

GnomAD3 genomes AF: 0.400 AC: 60776 AN: 151910 Hom.: 14675 Cov.: 32

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.427

Gnomad AMR AF: 0.465

Gnomad ASJ AF: 0.396

Gnomad EAS AF: 0.759

Gnomad SAS AF: 0.545

Gnomad FIN AF: 0.530

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.493

Gnomad OTH AF: 0.381

GnomAD2 exomes AF: 0.512 AC: 122102 AN: 238584 AF XY: 0.512

Gnomad AFR exome AF: 0.127

Gnomad AMR exome AF: 0.617

Gnomad ASJ exome AF: 0.414

Gnomad EAS exome AF: 0.772

Gnomad FIN exome AF: 0.527

Gnomad NFE exome AF: 0.495

Gnomad OTH exome AF: 0.494

GnomAD4 exome AF: 0.501 AC: 724115 AN: 1445818 Hom.: 186821 Cov.: 31 AF XY: 0.501 AC XY: 360444 AN XY: 719254

African (AFR) AF: 0.112 AC: 3650 AN: 32592

American (AMR) AF: 0.600 AC: 25596 AN: 42678

Ashkenazi Jewish (ASJ) AF: 0.412 AC: 10499 AN: 25508

East Asian (EAS) AF: 0.766 AC: 29698 AN: 38784

South Asian (SAS) AF: 0.534 AC: 44985 AN: 84302

European-Finnish (FIN) AF: 0.522 AC: 27719 AN: 53114

Middle Eastern (MID) AF: 0.321 AC: 1840 AN: 5726

European-Non Finnish (NFE) AF: 0.500 AC: 552226 AN: 1103370

Other (OTH) AF: 0.467 AC: 27902 AN: 59744

GnomAD4 genome AF: 0.400 AC: 60783 AN: 152028 Hom.: 14676 Cov.: 32 AF XY: 0.407 AC XY: 30212 AN XY: 74308

African (AFR) AF: 0.130 AC: 5373 AN: 41486

American (AMR) AF: 0.465 AC: 7107 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.396 AC: 1376 AN: 3472

East Asian (EAS) AF: 0.759 AC: 3928 AN: 5176

South Asian (SAS) AF: 0.546 AC: 2630 AN: 4818

European-Finnish (FIN) AF: 0.530 AC: 5598 AN: 10560

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.493 AC: 33482 AN: 67930

Other (OTH) AF: 0.381 AC: 803 AN: 2108

Alfa AF: 0.463 Hom.: 81896

Bravo AF: 0.387

Asia WGS AF: 0.613 AC: 2127 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	5.7
DANN	Benign	0.65
PhyloP100		-0.51
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00086
dbscSNV1_RF	Benign	0.16
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

Other links and lift over

dbSNP: rs6690037; hg19: chr1-207263829; COSMIC: COSV54690943; COSMIC: COSV54690943;