chr6-32029189-G-A

Position:

• chr6-32029189-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001002029.4(C4B):​c.3527G>A​(p.Ser1176Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 144,892 control chromosomes in the GnomAD database, including 1,657 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.11 (1657 hom., cov: 25)
  • Exomes 𝑓: 0.086 (18154 hom.)
  • Failed GnomAD Quality Control
• Consequence: C4B NM_001002029.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0520

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]

C4B (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), C4B. . Gene score misZ 2.0154 (greater than the threshold 3.09). Trascript score misZ 4.2643 (greater than threshold 3.09). GenCC has associacion of gene with complement component 4b deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0019135475).
• BP6: Variant 6-32029189-G-A is Benign according to our data. Variant chr6-32029189-G-A is described in ClinVar as [Benign]. Clinvar id is 402443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.25 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C4B	NM_001002029.4	c.3527G>A	p.Ser1176Asn	missense_variant	28/41	ENST00000435363.7	NP_001002029.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C4B	ENST00000435363.7	c.3527G>A	p.Ser1176Asn	missense_variant	28/41	1	NM_001002029.4	ENSP00000415941.2
C4B	ENST00000425700.3	c.3527G>A	p.Ser1176Asn	missense_variant	28/40	1		ENSP00000391933.2
C4B	ENST00000647698.1	c.2231G>A	p.Ser744Asn	missense_variant	18/31			ENSP00000497270.1
C4B	ENST00000648821.1	n.2140G>A		non_coding_transcript_exon_variant	15/27

Frequencies

GnomAD3 genomes AF: 0.109 AC: 15830 AN: 144772 Hom.: 1660 Cov.: 25

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.190

Gnomad AMR AF: 0.0832

Gnomad ASJ AF: 0.169

Gnomad EAS AF: 0.0612

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.0582

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.0902

Gnomad OTH AF: 0.127

GnomAD3 exomes AF: 0.0892 AC: 20773 AN: 232990 Hom.: 3111 AF XY: 0.0988 AC XY: 12453 AN XY: 126056

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.0550

Gnomad ASJ exome AF: 0.129

Gnomad EAS exome AF: 0.0496

Gnomad SAS exome AF: 0.244

Gnomad FIN exome AF: 0.0487

Gnomad NFE exome AF: 0.0639

Gnomad OTH exome AF: 0.0933

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0860 AC: 119172 AN: 1386406 Hom.: 18154 Cov.: 34 AF XY: 0.0910 AC XY: 62773 AN XY: 689566

Gnomad4 AFR exome AF: 0.142

Gnomad4 AMR exome AF: 0.0614

Gnomad4 ASJ exome AF: 0.151

Gnomad4 EAS exome AF: 0.0299

Gnomad4 SAS exome AF: 0.247

Gnomad4 FIN exome AF: 0.0562

Gnomad4 NFE exome AF: 0.0737

Gnomad4 OTH exome AF: 0.0965

GnomAD4 genome AF: 0.109 AC: 15835 AN: 144892 Hom.: 1657 Cov.: 25 AF XY: 0.110 AC XY: 7762 AN XY: 70616

Gnomad4 AFR AF: 0.144

Gnomad4 AMR AF: 0.0830

Gnomad4 ASJ AF: 0.169

Gnomad4 EAS AF: 0.0613

Gnomad4 SAS AF: 0.263

Gnomad4 FIN AF: 0.0582

Gnomad4 NFE AF: 0.0902

Gnomad4 OTH AF: 0.126

Alfa AF: 0.117 Hom.: 296

ExAC AF: 0.105 AC: 12703

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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: MAF -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.8
DANN	Benign	0.64
DEOGEN2	Benign	0.0017	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0019	N
MetaRNN	Benign	0.0019	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-1.4	N;.
PROVEAN	Benign	-0.040	N;N
REVEL	Benign	0.029
Sift	Benign	1.0	T;T
Sift4G	Benign	0.54	T;T
Polyphen		0.0	.;B
Vest4		0.14
ClinPred		0.000016	T
GERP RS		0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.049
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2746414; hg19: chr6-31996966; COSMIC: COSV70313427; COSMIC: COSV70313427;