1-207114136-C-T

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.179C>T(p.Ala60Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00499 in 1,613,178 control chromosomes in the GnomAD database, including 352 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.

• Frequency:
  • Genomes: 𝑓 0.026 (159 hom., cov: 31)
  • Exomes 𝑓: 0.0028 (193 hom.)
• Consequence: C4BPA NM_000715.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.54

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=0.0027171373).
• BP6: Variant 1-207114136-C-T is Benign according to our data. Variant chr1-207114136-C-T is described in ClinVar as [Benign]. Clinvar id is 775643.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0886 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C4BPA	NM_000715.4	c.179C>T	p.Ala60Val	missense_variant	3/12	ENST00000367070.8
C4BPA	XM_005273251.3	c.179C>T	p.Ala60Val	missense_variant	3/12
C4BPA	XM_005273252.5	c.179C>T	p.Ala60Val	missense_variant	3/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C4BPA	ENST00000367070.8	c.179C>T	p.Ala60Val	missense_variant	3/12	1	NM_000715.4	P1
C4BPA	ENST00000421786.5	c.179C>T	p.Ala60Val	missense_variant	3/5	4
C4BPA	ENST00000424088.1	c.179C>T	p.Ala60Val	missense_variant, NMD_transcript_variant	3/5	4

Frequencies

GnomAD3 genomes AF: 0.0263 AC: 3995 AN: 152006 Hom.: 159 Cov.: 31

Gnomad AFR AF: 0.0912

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0104

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0186

GnomAD3 exomes AF: 0.00679 AC: 1703 AN: 250926 Hom.: 81 AF XY: 0.00486 AC XY: 659 AN XY: 135676

Gnomad AFR exome AF: 0.0917

Gnomad AMR exome AF: 0.00471

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00295

GnomAD4 exome AF: 0.00277 AC: 4045 AN: 1461054 Hom.: 193 Cov.: 30 AF XY: 0.00238 AC XY: 1729 AN XY: 726878

Gnomad4 AFR exome AF: 0.0966

Gnomad4 AMR exome AF: 0.00562

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000371

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000112

Gnomad4 OTH exome AF: 0.00648

GnomAD4 genome AF: 0.0263 AC: 3999 AN: 152124 Hom.: 159 Cov.: 31 AF XY: 0.0254 AC XY: 1890 AN XY: 74372

Gnomad4 AFR AF: 0.0910

Gnomad4 AMR AF: 0.0104

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.0184

Alfa AF: 0.00478 Hom.: 60

Bravo AF: 0.0304

ESP6500AA AF: 0.0883 AC: 389

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00840 AC: 1020

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000297

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	0.088
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	0.26
Dann	Benign	0.90
DEOGEN2	Benign	0.038	T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0061	N
LIST_S2	Benign	0.34	T;T
MetaRNN	Benign	0.0027	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.64	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.085
Sift	Benign	1.0	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.0010	B;.
Vest4		0.025
MVP		0.088
MPC		0.25
ClinPred		0.0030	T
GERP RS		-6.5
Varity_R		0.078
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17020956; hg19: chr1-207287481;