1-207113035-C-G

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.10C>G(p.Pro4Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00399 in 1,597,298 control chromosomes in the GnomAD database, including 222 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P4Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.022 (120 hom., cov: 31)
  • Exomes 𝑓: 0.0021 (102 hom.)
• Consequence: C4BPA NM_000715.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.17

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=0.001934737).
• BP6: Variant 1-207113035-C-G is Benign according to our data. Variant chr1-207113035-C-G is described in ClinVar as [Benign]. Clinvar id is 780297.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0737 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C4BPA	NM_000715.4	c.10C>G	p.Pro4Ala	missense_variant	2/12	ENST00000367070.8
C4BPA	XM_005273251.3	c.10C>G	p.Pro4Ala	missense_variant	2/12
C4BPA	XM_005273252.5	c.10C>G	p.Pro4Ala	missense_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C4BPA	ENST00000367070.8	c.10C>G	p.Pro4Ala	missense_variant	2/12	1	NM_000715.4	P1
C4BPA	ENST00000421786.5	c.10C>G	p.Pro4Ala	missense_variant	2/5	4
C4BPA	ENST00000424088.1	c.10C>G	p.Pro4Ala	missense_variant, NMD_transcript_variant	2/5	4

Frequencies

GnomAD3 genomes AF: 0.0216 AC: 3280 AN: 152100 Hom.: 120 Cov.: 31

Gnomad AFR AF: 0.0761

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00557

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00584 AC: 1368 AN: 234326 Hom.: 54 AF XY: 0.00421 AC XY: 536 AN XY: 127270

Gnomad AFR exome AF: 0.0797

Gnomad AMR exome AF: 0.00302

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000715

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000202

Gnomad OTH exome AF: 0.00249

GnomAD4 exome AF: 0.00214 AC: 3090 AN: 1445080 Hom.: 102 Cov.: 31 AF XY: 0.00180 AC XY: 1291 AN XY: 718912

Gnomad4 AFR exome AF: 0.0806

Gnomad4 AMR exome AF: 0.00315

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000971

Gnomad4 SAS exome AF: 0.000108

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000732

Gnomad4 OTH exome AF: 0.00398

GnomAD4 genome AF: 0.0216 AC: 3281 AN: 152218 Hom.: 120 Cov.: 31 AF XY: 0.0206 AC XY: 1536 AN XY: 74432

Gnomad4 AFR AF: 0.0759

Gnomad4 AMR AF: 0.00556

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00120 Hom.: 5

Bravo AF: 0.0250

ESP6500AA AF: 0.0792 AC: 349

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00709 AC: 861

Asia WGS AF: 0.00578 AC: 20 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

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	0.012
Dann	Benign	0.43
DEOGEN2	Benign	0.067	T;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.30	T;T
MetaRNN	Benign	0.0019	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.013
Sift	Benign	0.16	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.022	B;.
Vest4		0.16
MVP		0.055
MPC		0.25
ClinPred		0.018	T
GERP RS		-6.7
Varity_R		0.026
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -37

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

Publications

LitVar

Other links and lift over

dbSNP: rs12072216; hg19: chr1-207286380;