1-207113054-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000715.4(C4BPA):c.29C>T(p.Ala10Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,456,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A10T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: C4BPA NM_000715.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.766

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.037314862).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C4BPA	NM_000715.4	c.29C>T	p.Ala10Val	missense_variant	2/12	ENST00000367070.8
C4BPA	XM_005273251.3	c.29C>T	p.Ala10Val	missense_variant	2/12
C4BPA	XM_005273252.5	c.29C>T	p.Ala10Val	missense_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C4BPA	ENST00000367070.8	c.29C>T	p.Ala10Val	missense_variant	2/12	1	NM_000715.4	P1
C4BPA	ENST00000421786.5	c.29C>T	p.Ala10Val	missense_variant	2/5	4
C4BPA	ENST00000424088.1	c.29C>T	p.Ala10Val	missense_variant, NMD_transcript_variant	2/5	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1456222 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 724438

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2022

The c.29C>T (p.A10V) alteration is located in exon 2 (coding exon 1) of the C4BPA gene. This alteration results from a C to T substitution at nucleotide position 29, causing the alanine (A) at amino acid position 10 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.23
Dann	Benign	0.076
DEOGEN2	Benign	0.043	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0065	N
LIST_S2	Benign	0.43	T;T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.037	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.050	N;N
REVEL	Benign	0.090
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0070	B;.
Vest4		0.097
MutPred		0.25		Loss of disorder (P = 0.0636);Loss of disorder (P = 0.0636);
MVP		0.040
MPC		0.26
ClinPred		0.036	T
GERP RS		-3.9
Varity_R		0.025
gMVP		0.10

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-207286399; COSMIC: COSV104674758;