1-207090484-A-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001017365.3(C4BPB):​c.232+3A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: C4BPB NM_001017365.3 splice_region, intron
• Scores: Splicing: ADA: 0.9988
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C4BPB	NM_001017365.3	MANE Select	c.232+3A>T		splice_region intron	N/A	NP_001017365.1	P20851-1
	C4BPB	NM_000716.3		c.232+3A>T		splice_region intron	N/A	NP_000707.1	P20851-1
	C4BPB	NM_001017367.1		c.232+3A>T		splice_region intron	N/A	NP_001017367.1	P20851-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C4BPB	ENST00000367078.8	TSL:1 MANE Select	c.232+3A>T		splice_region intron	N/A	ENSP00000356045.3	P20851-1
	C4BPB	ENST00000243611.9	TSL:1	c.232+3A>T		splice_region intron	N/A	ENSP00000243611.5	P20851-1
	C4BPB	ENST00000367076.7	TSL:1	c.229+3A>T		splice_region intron	N/A	ENSP00000356043.3	P20851-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1448120 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 720376

African (AFR) AF: 0.00 AC: 0 AN: 32620

American (AMR) AF: 0.00 AC: 0 AN: 42738

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25540

East Asian (EAS) AF: 0.00 AC: 0 AN: 38810

South Asian (SAS) AF: 0.00 AC: 0 AN: 84414

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53140

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105292

Other (OTH) AF: 0.00 AC: 0 AN: 59838

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	9.9
DANN	Benign	0.70
PhyloP100		-0.51

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.74
SpliceAI score (max)		0.62		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.62		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs6690037;

hg19: chr1-207263829;