1-207124335-T-C

Variant names:

• chr1-207124335-T-C
• rs1126618
• NM_000715.4:c.675T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000715.4(C4BPA):​c.675T>C​(p.Gly225Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.846 in 1,612,826 control chromosomes in the GnomAD database, including 578,171 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.86 (56324 hom., cov: 31)
  • Exomes 𝑓: 0.84 (521847 hom.)
• Consequence: C4BPA NM_000715.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.651

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

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-207124335-T-C is Benign according to our data. Variant chr1-207124335-T-C is described in ClinVar as [Benign]. Clinvar id is 402444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-207124335-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.651 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.897 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C4BPA	NM_000715.4	c.675T>C	p.Gly225Gly	synonymous_variant	Exon 6 of 12	ENST00000367070.8	NP_000706.1
C4BPA	XM_005273251.3	c.675T>C	p.Gly225Gly	synonymous_variant	Exon 6 of 12		XP_005273308.1
C4BPA	XM_005273252.5	c.675T>C	p.Gly225Gly	synonymous_variant	Exon 6 of 12		XP_005273309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C4BPA	ENST00000367070.8	c.675T>C	p.Gly225Gly	synonymous_variant	Exon 6 of 12	1	NM_000715.4	ENSP00000356037.3

Frequencies

GnomAD3 genomes AF: 0.859 AC: 130672 AN: 152038 Hom.: 56266 Cov.: 31

Gnomad AFR AF: 0.904

Gnomad AMI AF: 0.807

Gnomad AMR AF: 0.865

Gnomad ASJ AF: 0.767

Gnomad EAS AF: 0.796

Gnomad SAS AF: 0.878

Gnomad FIN AF: 0.880

Gnomad MID AF: 0.772

Gnomad NFE AF: 0.838

Gnomad OTH AF: 0.839

GnomAD2 exomes AF: 0.855 AC: 214046 AN: 250328 AF XY: 0.851

Gnomad AFR exome AF: 0.909

Gnomad AMR exome AF: 0.905

Gnomad ASJ exome AF: 0.771

Gnomad EAS exome AF: 0.812

Gnomad FIN exome AF: 0.882

Gnomad NFE exome AF: 0.837

Gnomad OTH exome AF: 0.835

GnomAD4 exome AF: 0.845 AC: 1233705 AN: 1460670 Hom.: 521847 Cov.: 40 AF XY: 0.845 AC XY: 613903 AN XY: 726728

African (AFR) AF: 0.904 AC: 30214 AN: 33434

American (AMR) AF: 0.902 AC: 40281 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.775 AC: 20250 AN: 26120

East Asian (EAS) AF: 0.788 AC: 31281 AN: 39672

South Asian (SAS) AF: 0.876 AC: 75561 AN: 86232

European-Finnish (FIN) AF: 0.884 AC: 47147 AN: 53340

Middle Eastern (MID) AF: 0.817 AC: 4703 AN: 5758

European-Non Finnish (NFE) AF: 0.841 AC: 934065 AN: 1111092

Other (OTH) AF: 0.832 AC: 50203 AN: 60348

GnomAD4 genome AF: 0.860 AC: 130791 AN: 152156 Hom.: 56324 Cov.: 31 AF XY: 0.862 AC XY: 64080 AN XY: 74364

African (AFR) AF: 0.904 AC: 37560 AN: 41530

American (AMR) AF: 0.865 AC: 13214 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.767 AC: 2662 AN: 3470

East Asian (EAS) AF: 0.796 AC: 4131 AN: 5190

South Asian (SAS) AF: 0.878 AC: 4230 AN: 4816

European-Finnish (FIN) AF: 0.880 AC: 9301 AN: 10574

Middle Eastern (MID) AF: 0.776 AC: 228 AN: 294

European-Non Finnish (NFE) AF: 0.838 AC: 56965 AN: 67996

Other (OTH) AF: 0.839 AC: 1767 AN: 2106

Alfa AF: 0.841 Hom.: 131086

Bravo AF: 0.860

Asia WGS AF: 0.812 AC: 2827 AN: 3478

EpiCase AF: 0.826

EpiControl AF: 0.826

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.6
DANN	Benign	0.41
PhyloP100		-0.65
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

Publications

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Other links and lift over

dbSNP: rs1126618; hg19: chr1-207297680; COSMIC: COSV65536467; COSMIC: COSV65536467;