1-207091721-A-C

Variant names:

• chr1-207091721-A-C
• NM_001017365.3:c.310A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001017365.3(C4BPB):​c.310A>C​(p.Thr104Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T104M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: C4BPB NM_001017365.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.13
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.310A>C	p.Thr104Pro	missense	Exon 4 of 7	NP_001017365.1	P20851-1
	C4BPB	NM_000716.3		c.310A>C	p.Thr104Pro	missense	Exon 3 of 6	NP_000707.1	P20851-1
	C4BPB	NM_001017367.1		c.310A>C	p.Thr104Pro	missense	Exon 4 of 7	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.310A>C	p.Thr104Pro	missense	Exon 4 of 7	ENSP00000356045.3	P20851-1
	C4BPB	ENST00000243611.9	TSL:1	c.310A>C	p.Thr104Pro	missense	Exon 3 of 6	ENSP00000243611.5	P20851-1
	C4BPB	ENST00000367076.7	TSL:1	c.307A>C	p.Thr103Pro	missense	Exon 3 of 6	ENSP00000356043.3	P20851-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	0.15
Eigen_PC	Benign	-0.084
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.51	T
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.46	T
MutationAssessor	Pathogenic	3.9	H
PhyloP100		1.1
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.036	D
Polyphen		0.98	D
Vest4		0.51
MutPred		0.64		Gain of loop (P = 0.1069)
MVP		0.30
MPC		0.70
ClinPred		0.83	D
GERP RS		3.9
Varity_R		0.88
gMVP		0.68
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

hg19: chr1-207265066;