6-32028747-C-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001002029.4(C4B):c.3285C>A(p.Gly1095=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 1,544,536 control chromosomes in the GnomAD database, including 36,154 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.19 (4578 hom., cov: 21)
  • Exomes 𝑓: 0.14 (31576 hom.)
• Consequence: C4B NM_001002029.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.647

Genes affected

C4B (HGNC:1324): (complement C4B (Chido/Rodgers blood group)) This gene encodes the basic form of complement factor 4, and together with the C4A gene, is part of the classical activation pathway. The protein is expressed as a single chain precursor which is proteolytically cleaved into a trimer of alpha, beta, and gamma chains prior to secretion. The trimer provides a surface for interaction between the antigen-antibody complex and other complement components. The alpha chain may be cleaved to release C4 anaphylatoxin, a mediator of local inflammation. Deficiency of this protein is associated with systemic lupus erythematosus. This gene localizes to the major histocompatibility complex (MHC) class III region on chromosome 6. Varying haplotypes of this gene cluster exist, such that individuals may have 1, 2, or 3 copies of this gene. In addition, this gene exists as a long form and a short form due to the presence or absence of a 6.4 kb endogenous HERV-K retrovirus in intron 9. [provided by RefSeq, May 2020]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 6-32028747-C-A is Benign according to our data. Variant chr6-32028747-C-A is described in ClinVar as [Benign]. Clinvar id is 2688520.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.647 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.361 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C4B	NM_001002029.4	c.3285C>A	p.Gly1095=	synonymous_variant	26/41	ENST00000435363.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C4B	ENST00000435363.7	c.3285C>A	p.Gly1095=	synonymous_variant	26/41	1	NM_001002029.4	P1
C4B	ENST00000425700.3	c.3285C>A	p.Gly1095=	synonymous_variant	26/40	1
C4B	ENST00000647698.1	c.1992C>A	p.Gly664=	synonymous_variant	16/31
C4B	ENST00000648821.1	n.1898C>A		non_coding_transcript_exon_variant	13/27

Frequencies

GnomAD3 genomes AF: 0.190 AC: 25694 AN: 135546 Hom.: 4565 Cov.: 21

Gnomad AFR AF: 0.366

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.0373

Gnomad MID AF: 0.238

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.218

GnomAD3 exomes AF: 0.149 AC: 33769 AN: 226874 Hom.: 5637 AF XY: 0.150 AC XY: 18483 AN XY: 123036

Gnomad AFR exome AF: 0.388

Gnomad AMR exome AF: 0.121

Gnomad ASJ exome AF: 0.104

Gnomad EAS exome AF: 0.152

Gnomad SAS exome AF: 0.243

Gnomad FIN exome AF: 0.0448

Gnomad NFE exome AF: 0.121

Gnomad OTH exome AF: 0.159

GnomAD4 exome AF: 0.139 AC: 196178 AN: 1408876 Hom.: 31576 Cov.: 33 AF XY: 0.141 AC XY: 98443 AN XY: 700612

Gnomad4 AFR exome AF: 0.378

Gnomad4 AMR exome AF: 0.129

Gnomad4 ASJ exome AF: 0.107

Gnomad4 EAS exome AF: 0.163

Gnomad4 SAS exome AF: 0.232

Gnomad4 FIN exome AF: 0.0450

Gnomad4 NFE exome AF: 0.128

Gnomad4 OTH exome AF: 0.158

GnomAD4 genome AF: 0.190 AC: 25734 AN: 135660 Hom.: 4578 Cov.: 21 AF XY: 0.188 AC XY: 12341 AN XY: 65548

Gnomad4 AFR AF: 0.366

Gnomad4 AMR AF: 0.184

Gnomad4 ASJ AF: 0.104

Gnomad4 EAS AF: 0.148

Gnomad4 SAS AF: 0.201

Gnomad4 FIN AF: 0.0373

Gnomad4 NFE AF: 0.119

Gnomad4 OTH AF: 0.216

Alfa AF: 0.148 Hom.: 656

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 20% of patients studied by a panel of primary immunodeficiencies. Number of patients: 18. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	8.5
Dann	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs406658; hg19: chr6-31996524; COSMIC: COSV70313311; COSMIC: COSV70313311;