6-32028996-A-G

Position:

chr6-32028996-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2

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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00024 ( 2 hom., cov: 23)

Exomes 𝑓: 0.00038 ( 52 hom. )

Consequence

C4B
NM_001002029.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 1.45

Variant links:

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 links:

C4B (HGNC:):

C4B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 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=0.1160346).

BP6

Variant 6-32028996-A-G is Benign according to our data. Variant chr6-32028996-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2362671.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C4B	NM_001002029.4 linkuse as main transcript	c.3439A>G	p.Ile1147Val	missense_variant	27/41	ENST00000435363.7	NP_001002029.3	P0C0L4P0C0L5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
C4B	ENST00000435363.7 linkuse as main transcript	c.3439A>G	p.Ile1147Val	missense_variant	27/41	1	NM_001002029.4	ENSP00000415941.2	P0C0L5
C4B	ENST00000425700.3 linkuse as main transcript	c.3439A>G	p.Ile1147Val	missense_variant	27/40	1		ENSP00000391933.2	F5GXS0
C4B	ENST00000647698.1 linkuse as main transcript	c.2143A>G	p.Ile715Val	missense_variant	17/31			ENSP00000497270.1	A0A3B3ISA6
C4B	ENST00000648821.1 linkuse as main transcript	n.2052A>G		non_coding_transcript_exon_variant	14/27

Frequencies

GnomAD3 genomes

AF:

0.000245

AC:

AN:

138812

Hom.:

Cov.:

show subpopulations

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:

AN:

232792

Hom.:

AF XY:

0.000150

AC XY:

AN XY:

127066

show subpopulations

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.:

Cov.:

AF XY:

0.000352

AC XY:

248

AN XY:

703928

show subpopulations

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:

AN:

138812

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

AN XY:

67086

show subpopulations

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.:

ExAC

AF:

0.000185

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

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. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2024

C4B: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.013

T;T

Eigen

Benign

-0.050

Eigen_PC

Benign

0.038

FATHMM_MKL

Benign

0.54

M_CAP

Benign

0.0078

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;.

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over