1-207091700-G-C

Variant names:

• chr1-207091700-G-C
• NM_001017365.3:c.289G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001017365.3(C4BPB):​c.289G>C​(p.Val97Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V97M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: C4BPB NM_001017365.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.80

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2135329).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C4BPB	NM_001017365.3	c.289G>C	p.Val97Leu	missense_variant	Exon 4 of 7	ENST00000367078.8	NP_001017365.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C4BPB	ENST00000367078.8	c.289G>C	p.Val97Leu	missense_variant	Exon 4 of 7	1	NM_001017365.3	ENSP00000356045.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461782 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	18
DANN	Benign	0.87
DEOGEN2	Benign	0.063	T;T;T;.;T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.071
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.76	.;T;.;T;T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.21	T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.94	L;.;L;.;L
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.91	N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.20	T;T;T;T;T
Sift4G	Pathogenic	0.0	D;T;D;D;D
Polyphen		0.49	P;.;P;B;P
Vest4		0.32
MutPred		0.60		Loss of glycosylation at S94 (P = 0.1069);Loss of glycosylation at S94 (P = 0.1069);Loss of glycosylation at S94 (P = 0.1069);.;Loss of glycosylation at S94 (P = 0.1069);
MVP		0.18
MPC		0.21
ClinPred		0.34	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.35

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-207265045;