6-32028502-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_001002029.4(C4B):c.3200C>T(p.Ala1067Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000938 in 1,535,454 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00037 (8 hom., cov: 18)
  • Exomes 𝑓: 0.000067 (13 hom.)
• Consequence: C4B NM_001002029.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.501

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 -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, C4B
• BP4: Computational evidence support a benign effect (MetaRNN=0.055594295).
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C4B	NM_001002029.4	c.3200C>T	p.Ala1067Val	missense_variant	25/41	ENST00000435363.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C4B	ENST00000435363.7	c.3200C>T	p.Ala1067Val	missense_variant	25/41	1	NM_001002029.4	P1
C4B	ENST00000425700.3	c.3200C>T	p.Ala1067Val	missense_variant	25/40	1
C4B	ENST00000647698.1	c.1907C>T	p.Ala636Val	missense_variant	15/31
C4B	ENST00000648821.1	n.1813C>T		non_coding_transcript_exon_variant	12/27

Frequencies

GnomAD3 genomes AF: 0.000366 AC: 50 AN: 136650 Hom.: 8 Cov.: 18

Gnomad AFR AF: 0.00110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000287

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: 0.0000641

Gnomad OTH AF: 0.000535

GnomAD3 exomes AF: 0.0000886 AC: 21 AN: 236980 Hom.: 0 AF XY: 0.0000779 AC XY: 10 AN XY: 128366

Gnomad AFR exome AF: 0.000951

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000338

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000472

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000672 AC: 94 AN: 1398804 Hom.: 13 Cov.: 31 AF XY: 0.0000646 AC XY: 45 AN XY: 696868

Gnomad4 AFR exome AF: 0.00107

Gnomad4 AMR exome AF: 0.0000917

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000357

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000396

Gnomad4 OTH exome AF: 0.000172

GnomAD4 genome AF: 0.000366 AC: 50 AN: 136650 Hom.: 8 Cov.: 18 AF XY: 0.000287 AC XY: 19 AN XY: 66180

Gnomad4 AFR AF: 0.00110

Gnomad4 AMR AF: 0.000287

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000641

Gnomad4 OTH AF: 0.000535

Alfa AF: 0.000192 Hom.: 0

ESP6500AA AF: 0.000924 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000136 AC: 16

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

Jul 15, 2021

The c.3200C>T (p.A1067V) alteration is located in exon 25 (coding exon 25) of the C4B gene. This alteration results from a C to T substitution at nucleotide position 3200, causing the alanine (A) at amino acid position 1067 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	Pathogenic	0.79
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.037	T;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.60	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.056	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	N;N
PROVEAN	Uncertain	-3.0	D;D
REVEL	Benign	0.15
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.65	.;P
Vest4		0.32
MVP		0.16
ClinPred		0.11	T
GERP RS		0.25
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.72
gMVP		0.77

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

LitVar

Other links and lift over

dbSNP: rs369928228; hg19: chr6-31996279;