6-32028700-G-A

Position:

chr6-32028700-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3

The NM_001002029.4(C4B):c.3238G>A(p.Ala1080Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000776 in 1,545,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000055 ( 0 hom., cov: 19)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

C4B
NM_001002029.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.20

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 Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.797

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C4B	NM_001002029.4 linkuse as main transcript	c.3238G>A	p.Ala1080Thr	missense_variant	26/41	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.3238G>A	p.Ala1080Thr	missense_variant	26/41	1	NM_001002029.4	ENSP00000415941.2	P0C0L5
C4B	ENST00000425700.3 linkuse as main transcript	c.3238G>A	p.Ala1080Thr	missense_variant	26/40	1		ENSP00000391933.2	F5GXS0
C4B	ENST00000647698.1 linkuse as main transcript	c.1942G>A	p.Ala648Thr	missense_variant	16/31			ENSP00000497270.1	A0A3B3ISA6
C4B	ENST00000648821.1 linkuse as main transcript	n.1851G>A		non_coding_transcript_exon_variant	13/27

Frequencies

GnomAD3 genomes

AF:

0.0000549

AC:

AN:

127400

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000204

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000219

AC:

AN:

228428

Hom.:

AF XY:

0.0000241

AC XY:

AN XY:

124702

show subpopulations

Gnomad AFR exome

AF:

0.000293

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:

0.0000100

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000353

AC:

AN:

1418250

Hom.:

Cov.:

AF XY:

0.00000283

AC XY:

AN XY:

705802

show subpopulations

Gnomad4 AFR exome

AF:

0.0000918

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.28e-7

Gnomad4 OTH exome

AF:

0.0000170

GnomAD4 genome

AF:

0.0000549

AC:

AN:

127518

Hom.:

Cov.:

AF XY:

0.0000490

AC XY:

AN XY:

61218

show subpopulations

Gnomad4 AFR

AF:

0.000204

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000338

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 15, 2024

The c.3238G>A (p.A1080T) alteration is located in exon 26 (coding exon 26) of the C4B gene. This alteration results from a G to A substitution at nucleotide position 3238, causing the alanine (A) at amino acid position 1080 to be replaced by a threonine (T). 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

0.76

BayesDel_addAF

Benign

-0.039

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.072

T;T

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.91

M_CAP

Benign

0.047

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Uncertain

-0.046

MutationAssessor

Pathogenic

3.8

H;.

PROVEAN

Uncertain

-3.5

D;D

REVEL

Uncertain

0.58

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

.;D

Vest4

0.64

MutPred

0.90

Gain of methylation at K1084 (P = 0.0941);Gain of methylation at K1084 (P = 0.0941);

MVP

0.57

ClinPred

0.99

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.89

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.24

Position offset: 15

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