1-207113064-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_000715.4(C4BPA):c.39A>G(p.Arg13=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00409 in 1,609,546 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0088 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (37 hom.)
• Consequence: C4BPA NM_000715.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.175

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 1-207113064-A-G is Benign according to our data. Variant chr1-207113064-A-G is described in ClinVar as [Benign]. Clinvar id is 711057.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.175 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00879 (1338/152218) while in subpopulation AFR AF= 0.0232 (962/41538). AF 95% confidence interval is 0.0219. There are 8 homozygotes in gnomad4. There are 643 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C4BPA	NM_000715.4	c.39A>G	p.Arg13=	synonymous_variant	2/12	ENST00000367070.8
C4BPA	XM_005273251.3	c.39A>G	p.Arg13=	synonymous_variant	2/12
C4BPA	XM_005273252.5	c.39A>G	p.Arg13=	synonymous_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C4BPA	ENST00000367070.8	c.39A>G	p.Arg13=	synonymous_variant	2/12	1	NM_000715.4	P1
C4BPA	ENST00000421786.5	c.39A>G	p.Arg13=	synonymous_variant	2/5	4
C4BPA	ENST00000424088.1	c.39A>G	p.Arg13=	synonymous_variant, NMD_transcript_variant	2/5	4

Frequencies

GnomAD3 genomes AF: 0.00878 AC: 1336 AN: 152100 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00472

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00347

Gnomad OTH AF: 0.0106

GnomAD3 exomes AF: 0.00451 AC: 1107 AN: 245598 Hom.: 10 AF XY: 0.00424 AC XY: 564 AN XY: 132924

Gnomad AFR exome AF: 0.0228

Gnomad AMR exome AF: 0.00336

Gnomad ASJ exome AF: 0.00341

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00301

Gnomad FIN exome AF: 0.00116

Gnomad NFE exome AF: 0.00402

Gnomad OTH exome AF: 0.00589

GnomAD4 exome AF: 0.00359 AC: 5238 AN: 1457328 Hom.: 37 Cov.: 31 AF XY: 0.00361 AC XY: 2615 AN XY: 724956

Gnomad4 AFR exome AF: 0.0271

Gnomad4 AMR exome AF: 0.00369

Gnomad4 ASJ exome AF: 0.00338

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00259

Gnomad4 FIN exome AF: 0.00124

Gnomad4 NFE exome AF: 0.00299

Gnomad4 OTH exome AF: 0.00586

GnomAD4 genome AF: 0.00879 AC: 1338 AN: 152218 Hom.: 8 Cov.: 32 AF XY: 0.00864 AC XY: 643 AN XY: 74426

Gnomad4 AFR AF: 0.0232

Gnomad4 AMR AF: 0.00471

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00347

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00507 Hom.: 7

Bravo AF: 0.00991

Asia WGS AF: 0.00260 AC: 9 AN: 3474

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
BayesDel_noAF	Benign	-0.93
Cadd	Benign	1.4
Dann	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs74867186; hg19: chr1-207286409;