6-32029189-G-A

Variant names:

• chr6-32029189-G-A
• rs2746414
• NM_001002029.4:c.3527G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• complement component 4b deficiency

  Inheritance: AR Classification: STRONG, NO_KNOWN Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• 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 VariationId 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 rank	MANE	Protein	UniProt
C4B	NM_001002029.4	c.3527G>A	p.Ser1176Asn	missense_variant	Exon 28 of 41	ENST00000435363.7	NP_001002029.3

Ensembl

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

GnomAD2 exomes AF: 0.0892 AC: 20773 AN: 232990 AF XY: 0.0988

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.142 AC: 4435 AN: 31170

American (AMR) AF: 0.0614 AC: 2594 AN: 42262

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 3609 AN: 23856

East Asian (EAS) AF: 0.0299 AC: 1173 AN: 39166

South Asian (SAS) AF: 0.247 AC: 20478 AN: 82820

European-Finnish (FIN) AF: 0.0562 AC: 2918 AN: 51886

Middle Eastern (MID) AF: 0.158 AC: 834 AN: 5294

European-Non Finnish (NFE) AF: 0.0737 AC: 77602 AN: 1052670

Other (OTH) AF: 0.0965 AC: 5529 AN: 57282

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.144 AC: 5690 AN: 39490

American (AMR) AF: 0.0830 AC: 1201 AN: 14474

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 560 AN: 3316

East Asian (EAS) AF: 0.0613 AC: 304 AN: 4956

South Asian (SAS) AF: 0.263 AC: 1175 AN: 4476

European-Finnish (FIN) AF: 0.0582 AC: 572 AN: 9832

Middle Eastern (MID) AF: 0.139 AC: 37 AN: 266

European-Non Finnish (NFE) AF: 0.0902 AC: 5887 AN: 65258

Other (OTH) AF: 0.126 AC: 249 AN: 1984

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

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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: 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;.
PhyloP100		0.052
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
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2746414; hg19: chr6-31996966; COSMIC: COSV70313427; COSMIC: COSV70313427;