rs4844573

Variant names:

• chr1-207131555-T-C
• rs4844573
• NM_000715.4:c.899T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000715.4(C4BPA):​c.899T>C​(p.Ile300Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 1,602,050 control chromosomes in the GnomAD database, including 119,930 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (19783 hom., cov: 31)
  • Exomes 𝑓: 0.36 (100147 hom.)
• Consequence: C4BPA NM_000715.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.58
• Publications: 46 publications found

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]

ENSG00000296591 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0640223E-6).
• BP6: Variant 1-207131555-T-C is Benign according to our data. Variant chr1-207131555-T-C is described in ClinVar as Benign. ClinVar VariationId is 402445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.754 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000715.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C4BPA	NM_000715.4	MANE Select	c.899T>C	p.Ile300Thr	missense	Exon 8 of 12	NP_000706.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C4BPA	ENST00000367070.8	TSL:1 MANE Select	c.899T>C	p.Ile300Thr	missense	Exon 8 of 12	ENSP00000356037.3
	ENSG00000296591	ENST00000740658.1		n.204-1281A>G		intron	N/A
	ENSG00000296591	ENST00000740659.1		n.285-1281A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.476 AC: 72257 AN: 151802 Hom.: 19736 Cov.: 31

Gnomad AFR AF: 0.761

Gnomad AMI AF: 0.399

Gnomad AMR AF: 0.432

Gnomad ASJ AF: 0.306

Gnomad EAS AF: 0.274

Gnomad SAS AF: 0.347

Gnomad FIN AF: 0.463

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.350

Gnomad OTH AF: 0.443

GnomAD2 exomes AF: 0.392 AC: 97429 AN: 248352 AF XY: 0.381

Gnomad AFR exome AF: 0.769

Gnomad AMR exome AF: 0.428

Gnomad ASJ exome AF: 0.306

Gnomad EAS exome AF: 0.291

Gnomad FIN exome AF: 0.466

Gnomad NFE exome AF: 0.350

Gnomad OTH exome AF: 0.377

GnomAD4 exome AF: 0.363 AC: 526452 AN: 1450130 Hom.: 100147 Cov.: 30 AF XY: 0.361 AC XY: 260456 AN XY: 722064

African (AFR) AF: 0.777 AC: 25691 AN: 33082

American (AMR) AF: 0.427 AC: 18949 AN: 44336

Ashkenazi Jewish (ASJ) AF: 0.306 AC: 7942 AN: 25980

East Asian (EAS) AF: 0.307 AC: 12143 AN: 39546

South Asian (SAS) AF: 0.346 AC: 29638 AN: 85740

European-Finnish (FIN) AF: 0.454 AC: 24204 AN: 53320

Middle Eastern (MID) AF: 0.404 AC: 2316 AN: 5734

European-Non Finnish (NFE) AF: 0.348 AC: 383234 AN: 1102408

Other (OTH) AF: 0.372 AC: 22335 AN: 59984

GnomAD4 genome AF: 0.476 AC: 72375 AN: 151920 Hom.: 19783 Cov.: 31 AF XY: 0.474 AC XY: 35177 AN XY: 74256

African (AFR) AF: 0.761 AC: 31553 AN: 41438

American (AMR) AF: 0.431 AC: 6576 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.306 AC: 1060 AN: 3468

East Asian (EAS) AF: 0.275 AC: 1417 AN: 5152

South Asian (SAS) AF: 0.347 AC: 1667 AN: 4808

European-Finnish (FIN) AF: 0.463 AC: 4885 AN: 10548

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.350 AC: 23811 AN: 67940

Other (OTH) AF: 0.444 AC: 937 AN: 2112

Alfa AF: 0.387 Hom.: 29435

Bravo AF: 0.489

TwinsUK AF: 0.350 AC: 1296

ALSPAC AF: 0.340 AC: 1311

ESP6500AA AF: 0.753 AC: 3316

ESP6500EA AF: 0.347 AC: 2980

ExAC AF: 0.396 AC: 48051

Asia WGS AF: 0.336 AC: 1170 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.055
DANN	Benign	0.32
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.051	T
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.73	N
PhyloP100		-2.6
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.62	N
REVEL	Benign	0.12
Sift	Benign	0.92	T
Sift4G	Benign	0.87	T
Polyphen		0.0	B
Vest4		0.0080
MPC		0.32
ClinPred		0.0031	T
GERP RS		-8.9
Varity_R		0.030
gMVP		0.20
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4844573; hg19: chr1-207304900; COSMIC: COSV65535741; COSMIC: COSV65535741;