1-207113036-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000715.4(C4BPA):c.11C>A(p.Pro4Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.039 in 1,596,536 control chromosomes in the GnomAD database, including 1,533 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P4A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.033 (142 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1391 hom.)
• Consequence: C4BPA NM_000715.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.52

Genes affected

C4BPA (HGNC:1325): (complement component 4 binding protein alpha) This gene encodes a member of a superfamily of proteins composed predominantly of tandemly arrayed short consensus repeats of approximately 60 amino acids. Along with a single, unique beta-chain, seven identical alpha-chains encoded by this gene assemble into the predominant isoform of C4b-binding protein, a multimeric protein that controls activation of the complement cascade through the classical pathway. 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. Two pseudogenes of this gene are also found in the cluster. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002055645).
• BP6: Variant 1-207113036-C-A is Benign according to our data. Variant chr1-207113036-C-A is described in ClinVar as [Benign]. Clinvar id is 1229349.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0792 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C4BPA	NM_000715.4	c.11C>A	p.Pro4Gln	missense_variant	2/12	ENST00000367070.8
C4BPA	XM_005273251.3	c.11C>A	p.Pro4Gln	missense_variant	2/12
C4BPA	XM_005273252.5	c.11C>A	p.Pro4Gln	missense_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C4BPA	ENST00000367070.8	c.11C>A	p.Pro4Gln	missense_variant	2/12	1	NM_000715.4	P1
C4BPA	ENST00000421786.5	c.11C>A	p.Pro4Gln	missense_variant	2/5	4
C4BPA	ENST00000424088.1	c.11C>A	p.Pro4Gln	missense_variant, NMD_transcript_variant	2/5	4

Frequencies

GnomAD3 genomes AF: 0.0333 AC: 5070 AN: 152100 Hom.: 142 Cov.: 32

Gnomad AFR AF: 0.00876

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0826

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0796

Gnomad FIN AF: 0.0192

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0394

Gnomad OTH AF: 0.0340

GnomAD3 exomes AF: 0.0409 AC: 9504 AN: 232520 Hom.: 298 AF XY: 0.0426 AC XY: 5385 AN XY: 126284

Gnomad AFR exome AF: 0.00838

Gnomad AMR exome AF: 0.0803

Gnomad ASJ exome AF: 0.0250

Gnomad EAS exome AF: 0.00264

Gnomad SAS exome AF: 0.0844

Gnomad FIN exome AF: 0.0188

Gnomad NFE exome AF: 0.0358

Gnomad OTH exome AF: 0.0376

GnomAD4 exome AF: 0.0396 AC: 57245 AN: 1444318 Hom.: 1391 Cov.: 31 AF XY: 0.0412 AC XY: 29578 AN XY: 718472

Gnomad4 AFR exome AF: 0.00626

Gnomad4 AMR exome AF: 0.0795

Gnomad4 ASJ exome AF: 0.0259

Gnomad4 EAS exome AF: 0.00337

Gnomad4 SAS exome AF: 0.0875

Gnomad4 FIN exome AF: 0.0215

Gnomad4 NFE exome AF: 0.0383

Gnomad4 OTH exome AF: 0.0366

GnomAD4 genome AF: 0.0333 AC: 5073 AN: 152218 Hom.: 142 Cov.: 32 AF XY: 0.0337 AC XY: 2506 AN XY: 74436

Gnomad4 AFR AF: 0.00874

Gnomad4 AMR AF: 0.0830

Gnomad4 ASJ AF: 0.0248

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0792

Gnomad4 FIN AF: 0.0192

Gnomad4 NFE AF: 0.0394

Gnomad4 OTH AF: 0.0336

Alfa AF: 0.0367 Hom.: 181

Bravo AF: 0.0349

TwinsUK AF: 0.0367 AC: 136

ALSPAC AF: 0.0436 AC: 168

ESP6500AA AF: 0.0109 AC: 48

ESP6500EA AF: 0.0358 AC: 308

ExAC AF: 0.0408 AC: 4958

Asia WGS AF: 0.0270 AC: 96 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	7.6
Dann	Benign	0.26
DEOGEN2	Benign	0.047	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.27	T;T
MetaRNN	Benign	0.0021	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.017
Sift	Benign	0.50	T;T
Sift4G	Benign	0.50	T;T
Polyphen		0.048	B;.
Vest4		0.10
MPC		0.36
ClinPred		0.0012	T
GERP RS		2.4
Varity_R		0.034
gMVP		0.16

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

LitVar

Other links and lift over

dbSNP: rs55867570; hg19: chr1-207286381; COSMIC: COSV65538019;