6-32029623-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Strong BP6_Moderate

The NM_001002029.4(C4B):c.3734C>T(p.Pro1245Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000281 in 149,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P1245P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 27)
  • Exomes 𝑓: 0.000075 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: C4B NM_001002029.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.14

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=0.01269719).
• BP6: Variant 6-32029623-C-T is Benign according to our data. Variant chr6-32029623-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3136010.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C4B	NM_001002029.4	c.3734C>T	p.Pro1245Leu	missense_variant	29/41	ENST00000435363.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C4B	ENST00000435363.7	c.3734C>T	p.Pro1245Leu	missense_variant	29/41	1	NM_001002029.4	P1

Frequencies

GnomAD3 genomes AF: 0.000281 AC: 42 AN: 149482 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.000905

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000664

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000214

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000150

Gnomad OTH AF: 0.000985

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000748 AC: 109 AN: 1457394 Hom.: 0 Cov.: 35 AF XY: 0.0000552 AC XY: 40 AN XY: 724970

Gnomad4 AFR exome AF: 0.00184

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.000299

GnomAD4 genome AF: 0.000281 AC: 42 AN: 149586 Hom.: 0 Cov.: 27 AF XY: 0.000302 AC XY: 22 AN XY: 72870

Gnomad4 AFR AF: 0.000903

Gnomad4 AMR AF: 0.0000663

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000214

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000150

Gnomad4 OTH AF: 0.000975

Alfa AF: 0.000337 Hom.: 0

ExAC AF: 0.000266 AC: 31

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	0.0070
Dann	Benign	0.89
DEOGEN2	Benign	0.0041	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0014	N
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.53	N;.
MutationTaster	Benign	1.0	N;N
PROVEAN	Benign	0.52	N;N
REVEL	Benign	0.040
Sift	Benign	0.98	T;T
Sift4G	Benign	0.75	T;T
Polyphen		0.0020	.;B
Vest4		0.037
MVP		0.27
ClinPred		0.015	T
GERP RS		-3.9
Varity_R		0.019
gMVP		0.25

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: rs746665484; hg19: chr6-31997400; COSMIC: COSV101312128; COSMIC: COSV101312128;