1-207124331-T-C

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.671T>C(p.Ile224Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00256 in 1,613,690 control chromosomes in the GnomAD database, including 96 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (52 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (44 hom.)
• Consequence: C4BPA NM_000715.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.42

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=0.004507065).
• BP6: Variant 1-207124331-T-C is Benign according to our data. Variant chr1-207124331-T-C is described in ClinVar as [Benign]. Clinvar id is 783303.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0135 (2059/152246) while in subpopulation AFR AF= 0.0459 (1907/41532). AF 95% confidence interval is 0.0442. There are 52 homozygotes in gnomad4. There are 998 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 52 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C4BPA	NM_000715.4	c.671T>C	p.Ile224Thr	missense_variant	6/12	ENST00000367070.8
C4BPA	XM_005273251.3	c.671T>C	p.Ile224Thr	missense_variant	6/12
C4BPA	XM_005273252.5	c.671T>C	p.Ile224Thr	missense_variant	6/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C4BPA	ENST00000367070.8	c.671T>C	p.Ile224Thr	missense_variant	6/12	1	NM_000715.4	P1

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2056 AN: 152128 Hom.: 52 Cov.: 32

Gnomad AFR AF: 0.0460

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00714

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00351 AC: 880 AN: 250444 Hom.: 23 AF XY: 0.00270 AC XY: 365 AN XY: 135350

Gnomad AFR exome AF: 0.0477

Gnomad AMR exome AF: 0.00255

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000885

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00142 AC: 2077 AN: 1461444 Hom.: 44 Cov.: 33 AF XY: 0.00122 AC XY: 885 AN XY: 727052

Gnomad4 AFR exome AF: 0.0481

Gnomad4 AMR exome AF: 0.00336

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000828

Gnomad4 OTH exome AF: 0.00341

GnomAD4 genome AF: 0.0135 AC: 2059 AN: 152246 Hom.: 52 Cov.: 32 AF XY: 0.0134 AC XY: 998 AN XY: 74440

Gnomad4 AFR AF: 0.0459

Gnomad4 AMR AF: 0.00713

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00994

Alfa AF: 0.00605 Hom.: 7

Bravo AF: 0.0159

ESP6500AA AF: 0.0424 AC: 187

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00433 AC: 526

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000594

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
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	0.093
Dann	Benign	0.43
DEOGEN2	Benign	0.041	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.72	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.074
Sift	Benign	0.24	T
Sift4G	Benign	0.20	T
Polyphen		0.0030	B
Vest4		0.019
MVP		0.12
MPC		0.32
ClinPred		0.011	T
GERP RS		-7.3
Varity_R		0.052
gMVP		0.35

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: rs116795518; hg19: chr1-207297676;