6-32017141-C-A

Position:

• chr6-32017141-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2 BP4 BP6_Moderate

The NM_001002029.4(C4B):​c.1040C>A​(p.Ser347Tyr) variant causes a missense change. In-silico tool predicts 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: not found (cov: 0)
• Consequence: C4B NM_001002029.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.71

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 Likely_benign. Variant got -2 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=0.33539784).
• BP6: Variant 6-32017141-C-A is Benign according to our data. Variant chr6-32017141-C-A is described in ClinVar as [Benign]. Clinvar id is 982136.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C4B	NM_001002029.4	c.1040C>A	p.Ser347Tyr	missense_variant	9/41	ENST00000435363.7	NP_001002029.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C4B	ENST00000435363.7	c.1040C>A	p.Ser347Tyr	missense_variant	9/41	1	NM_001002029.4	ENSP00000415941.2
C4B	ENST00000425700.3	c.1040C>A	p.Ser347Tyr	missense_variant	9/40	1		ENSP00000391933.2
C4B	ENST00000485543.1	n.*5C>A		downstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Pathology and Clinical Laboratory Medicine, King Fahad Medical City

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.071	T;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.34	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	2.9	M;.
PROVEAN	Uncertain	-3.0	D;D
REVEL	Benign	0.12
Sift	Benign	0.070	T;T
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.99	.;D
Vest4		0.42
MutPred		0.30		Loss of glycosylation at S347 (P = 0.0168);Loss of glycosylation at S347 (P = 0.0168);
MVP		0.59
ClinPred		0.98	D
GERP RS		2.9
Varity_R		0.62
gMVP		0.41

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: rs139889867; hg19: chr6-31984918; COSMIC: COSV70931209; COSMIC: COSV70931209;