1-207115437-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000715.4(C4BPA):c.350G>A(p.Gly117Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: C4BPA NM_000715.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.44

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.775

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C4BPA	NM_000715.4	c.350G>A	p.Gly117Glu	missense_variant	4/12	ENST00000367070.8
C4BPA	XM_005273251.3	c.350G>A	p.Gly117Glu	missense_variant	4/12
C4BPA	XM_005273252.5	c.350G>A	p.Gly117Glu	missense_variant	4/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C4BPA	ENST00000367070.8	c.350G>A	p.Gly117Glu	missense_variant	4/12	1	NM_000715.4	P1
C4BPA	ENST00000421786.5	c.350G>A	p.Gly117Glu	missense_variant	4/5	4
C4BPA	ENST00000424088.1	c.*89G>A		3_prime_UTR_variant, NMD_transcript_variant	5/5	4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 31

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

Aug 12, 2021

The c.350G>A (p.G117E) alteration is located in exon 4 (coding exon 3) of the C4BPA gene. This alteration results from a G to A substitution at nucleotide position 350, causing the glycine (G) at amino acid position 117 to be replaced by a glutamic acid (E). 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	0.28
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.055	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-6.5	D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0040	D;T
Sift4G	Uncertain	0.0060	D;T
Polyphen		1.0	D;.
Vest4		0.59
MutPred		0.58		Gain of disorder (P = 0.0913);Gain of disorder (P = 0.0913);
MVP		0.75
MPC		1.0
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.85
gMVP		0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-207288782;