rs45574833

Positions:

• chr1-207126725-G-A
• chr1-207126725-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000715.4(C4BPA):​c.719G>A​(p.Arg240His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 1,605,946 control chromosomes in the GnomAD database, including 307 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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.

• Frequency:
  • Genomes: 𝑓 0.013 (38 hom., cov: 32)
  • Exomes 𝑓: 0.014 (269 hom.)
• Consequence: C4BPA NM_000715.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.60

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=0.0035045445).
• BP6: Variant 1-207126725-G-A is Benign according to our data. Variant chr1-207126725-G-A is described in ClinVar as [Benign]. Clinvar id is 1175658.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0134 (2035/152002) while in subpopulation NFE AF= 0.017 (1154/68002). AF 95% confidence interval is 0.0162. There are 38 homozygotes in gnomad4. There are 1097 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 38 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C4BPA	NM_000715.4	c.719G>A	p.Arg240His	missense_variant	7/12	ENST00000367070.8
C4BPA	XM_005273251.3	c.719G>A	p.Arg240His	missense_variant	7/12
C4BPA	XM_005273252.5	c.719G>A	p.Arg240His	missense_variant	7/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C4BPA	ENST00000367070.8	c.719G>A	p.Arg240His	missense_variant	7/12	1	NM_000715.4	P1

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 2035 AN: 151884 Hom.: 38 Cov.: 32

Gnomad AFR AF: 0.00269

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00374

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.0602

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0170

Gnomad OTH AF: 0.0106

GnomAD3 exomes AF: 0.0143 AC: 3522 AN: 247038 Hom.: 55 AF XY: 0.0144 AC XY: 1922 AN XY: 133504

Gnomad AFR exome AF: 0.00162

Gnomad AMR exome AF: 0.00270

Gnomad ASJ exome AF: 0.00619

Gnomad EAS exome AF: 0.0000550

Gnomad SAS exome AF: 0.00393

Gnomad FIN exome AF: 0.0585

Gnomad NFE exome AF: 0.0167

Gnomad OTH exome AF: 0.0141

GnomAD4 exome AF: 0.0138 AC: 20034 AN: 1453944 Hom.: 269 Cov.: 29 AF XY: 0.0138 AC XY: 9973 AN XY: 723220

Gnomad4 AFR exome AF: 0.00132

Gnomad4 AMR exome AF: 0.00281

Gnomad4 ASJ exome AF: 0.00766

Gnomad4 EAS exome AF: 0.0000507

Gnomad4 SAS exome AF: 0.00455

Gnomad4 FIN exome AF: 0.0573

Gnomad4 NFE exome AF: 0.0140

Gnomad4 OTH exome AF: 0.0122

GnomAD4 genome AF: 0.0134 AC: 2035 AN: 152002 Hom.: 38 Cov.: 32 AF XY: 0.0148 AC XY: 1097 AN XY: 74280

Gnomad4 AFR AF: 0.00268

Gnomad4 AMR AF: 0.00374

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.0602

Gnomad4 NFE AF: 0.0170

Gnomad4 OTH AF: 0.0105

Alfa AF: 0.0143 Hom.: 40

Bravo AF: 0.00819

TwinsUK AF: 0.0113 AC: 42

ALSPAC AF: 0.0153 AC: 59

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0129 AC: 111

ExAC AF: 0.0139 AC: 1687

Asia WGS AF: 0.00318 AC: 12 AN: 3478

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

This variant is associated with the following publications: (PMID: 18424762) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	1.2
DANN	Benign	0.28
DEOGEN2	Benign	0.033	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0055	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.26	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.42	N
REVEL	Benign	0.020
Sift	Benign	0.58	T
Sift4G	Benign	0.78	T
Polyphen		0.0	B
Vest4		0.054
MPC		0.31
ClinPred		0.000020	T
GERP RS		-2.0
Varity_R		0.019
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs45574833; hg19: chr1-207300070; COSMIC: COSV65537875; COSMIC: COSV65537875;