6-32028996-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_001002029.4(C4B):c.3439A>G(p.Ile1147Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000368 in 1,552,536 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (2 hom., cov: 23)
  • Exomes 𝑓: 0.00038 (52 hom.)
• Consequence: C4B NM_001002029.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.45

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 Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, C4B
• BP4: Computational evidence support a benign effect (MetaRNN=0.1160346).
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C4B	NM_001002029.4	c.3439A>G	p.Ile1147Val	missense_variant	27/41	ENST00000435363.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C4B	ENST00000435363.7	c.3439A>G	p.Ile1147Val	missense_variant	27/41	1	NM_001002029.4	P1
C4B	ENST00000425700.3	c.3439A>G	p.Ile1147Val	missense_variant	27/40	1
C4B	ENST00000647698.1	c.2146A>G	p.Ile716Val	missense_variant	17/31
C4B	ENST00000648821.1	n.2052A>G		non_coding_transcript_exon_variant	14/27

Frequencies

GnomAD3 genomes AF: 0.000245 AC: 34 AN: 138812 Hom.: 2 Cov.: 23

Gnomad AFR AF: 0.000237

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000706

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000155 AC: 36 AN: 232792 Hom.: 4 AF XY: 0.000150 AC XY: 19 AN XY: 127066

Gnomad AFR exome AF: 0.000142

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000314

Gnomad OTH exome AF: 0.000345

GnomAD4 exome AF: 0.000381 AC: 538 AN: 1413724 Hom.: 52 Cov.: 31 AF XY: 0.000352 AC XY: 248 AN XY: 703928

Gnomad4 AFR exome AF: 0.000152

Gnomad4 AMR exome AF: 0.0000226

Gnomad4 ASJ exome AF: 0.0000385

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000473

Gnomad4 OTH exome AF: 0.000392

GnomAD4 genome AF: 0.000245 AC: 34 AN: 138812 Hom.: 2 Cov.: 23 AF XY: 0.000149 AC XY: 10 AN XY: 67086

Gnomad4 AFR AF: 0.000237

Gnomad4 AMR AF: 0.0000706

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000288 Hom.: 0

ExAC AF: 0.000185 AC: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2022

The c.3439A>G (p.I1147V) alteration is located in exon 27 (coding exon 27) of the C4B gene. This alteration results from a A to G substitution at nucleotide position 3439, causing the isoleucine (I) at amino acid position 1147 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.013	T;T
Eigen	Benign	-0.050
Eigen_PC	Benign	0.038
FATHMM_MKL	Benign	0.54	D
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	0.97	N;N
PROVEAN	Benign	-0.26	N;N
REVEL	Benign	0.10
Sift	Benign	0.19	T;T
Sift4G	Benign	0.48	T;T
Polyphen		0.28	.;B
Vest4		0.25
MVP		0.11
ClinPred		0.025	T
GERP RS		3.2
Varity_R		0.11
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs781626894; hg19: chr6-31996773;