1-207113122-C-G

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.97C>G(p.Leu33Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00213 in 1,611,538 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (35 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (42 hom.)
• Consequence: C4BPA NM_000715.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.305

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=0.0046460032).
• BP6: Variant 1-207113122-C-G is Benign according to our data. Variant chr1-207113122-C-G is described in ClinVar as [Benign]. Clinvar id is 787219.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0115 (1757/152248) while in subpopulation AFR AF= 0.0402 (1670/41548). AF 95% confidence interval is 0.0386. There are 35 homozygotes in gnomad4. There are 838 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 35 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C4BPA	NM_000715.4	c.97C>G	p.Leu33Val	missense_variant	2/12	ENST00000367070.8
C4BPA	XM_005273251.3	c.97C>G	p.Leu33Val	missense_variant	2/12
C4BPA	XM_005273252.5	c.97C>G	p.Leu33Val	missense_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C4BPA	ENST00000367070.8	c.97C>G	p.Leu33Val	missense_variant	2/12	1	NM_000715.4	P1
C4BPA	ENST00000421786.5	c.97C>G	p.Leu33Val	missense_variant	2/5	4
C4BPA	ENST00000424088.1	c.97C>G	p.Leu33Val	missense_variant, NMD_transcript_variant	2/5	4

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1754 AN: 152130 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.0402

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00274 AC: 678 AN: 247396 Hom.: 21 AF XY: 0.00182 AC XY: 244 AN XY: 133812

Gnomad AFR exome AF: 0.0398

Gnomad AMR exome AF: 0.000929

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000332

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.00117

GnomAD4 exome AF: 0.00115 AC: 1678 AN: 1459290 Hom.: 42 Cov.: 31 AF XY: 0.000997 AC XY: 724 AN XY: 725942

Gnomad4 AFR exome AF: 0.0438

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00216

GnomAD4 genome AF: 0.0115 AC: 1757 AN: 152248 Hom.: 35 Cov.: 32 AF XY: 0.0113 AC XY: 838 AN XY: 74470

Gnomad4 AFR AF: 0.0402

Gnomad4 AMR AF: 0.00406

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.00199 Hom.: 1

Bravo AF: 0.0134

ESP6500AA AF: 0.0397 AC: 175

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00351 AC: 426

Asia WGS AF: 0.000867 AC: 3 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.077	T;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.79	T;T
MetaRNN	Benign	0.0046	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	0.98	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.46
MVP		0.45
MPC		0.91
ClinPred		0.043	T
GERP RS		4.0
Varity_R		0.33
gMVP		0.39

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: rs116810489; hg19: chr1-207286467;