NM_001002029.4:c.4054C>A

Variant names:

• chr6-32030025-C-A
• rs1435006597
• NM_001002029.4:c.4054C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001002029.4(C4B):​c.4054C>A​(p.Arg1352Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1352L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 27)
• Consequence: C4B NM_001002029.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.173

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.046587676).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C4B	NM_001002029.4	c.4054C>A	p.Arg1352Ser	missense_variant	Exon 30 of 41	ENST00000435363.7	NP_001002029.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C4B	ENST00000435363.7	c.4054C>A	p.Arg1352Ser	missense_variant	Exon 30 of 41	1	NM_001002029.4	ENSP00000415941.2

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 27

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4054C>A (p.R1352S) alteration is located in exon 30 (coding exon 30) of the C4B gene. This alteration results from a C to A substitution at nucleotide position 4054, causing the arginine (R) at amino acid position 1352 to be replaced by a serine (S). 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	0.12
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	4.5
DANN	Benign	0.53
DEOGEN2	Benign	0.0030	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0080	N
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.047	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.34	N;.
PhyloP100		-0.17
PROVEAN	Benign	0.020	N;N
REVEL	Benign	0.013
Sift	Benign	0.39	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.0	.;B
Vest4		0.068
MutPred		0.46		Loss of MoRF binding (P = 0.0342);Loss of MoRF binding (P = 0.0342);
MVP		0.055
ClinPred		0.026	T
GERP RS		-5.7
Varity_R		0.24
gMVP		0.29
Mutation Taster		=93/7	polymorphism

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

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Other links and lift over

dbSNP: rs1435006597; hg19: chr6-31997802;