Genetic Variant NM_006509.4:c.28C>A (chr19-45001607-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006509.4(RELB):c.28C>A(p.Pro10Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000022 in 1,362,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

RELB
NM_006509.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.83

Publications

0 publications found

Variant links:

Genes affected

RELB (HGNC:9956): (RELB proto-oncogene, NF-kB subunit) Enables RNA polymerase II cis-regulatory region sequence-specific DNA binding activity and protein kinase binding activity. Involved in lymphocyte differentiation and negative regulation of interferon-beta production. Located in cytosol and nucleoplasm. Part of chromatin; nucleus; and transcription repressor complex. Colocalizes with centrosome. Implicated in breast cancer and immunodeficiency 53. Biomarker of breast cancer and transitional cell carcinoma. [provided by Alliance of Genome Resources, Apr 2022]

RELB Gene-Disease associations (from GenCC):

immunodeficiency 53
Inheritance: AR, Unknown Classification: LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

RELB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09626782).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006509.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELB	NM_006509.4	MANE Select	c.28C>A	p.Pro10Thr	missense	Exon 1 of 12	NP_006500.2
	RELB	NM_001411087.1		c.28C>A	p.Pro10Thr	missense	Exon 1 of 11	NP_001398016.1	D6R992

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RELB	ENST00000221452.13	TSL:1 MANE Select	c.28C>A	p.Pro10Thr	missense	Exon 1 of 12	ENSP00000221452.7	Q01201
RELB	ENST00000505236.2	TSL:5	c.28C>A	p.Pro10Thr	missense	Exon 1 of 11	ENSP00000423287.1	D6R992
RELB	ENST00000509480.5	TSL:3	n.28C>A		non_coding_transcript_exon	Exon 1 of 5	ENSP00000427348.1	D6RIV7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

111144

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000220

AC:

AN:

1362466

Hom.:

Cov.:

AF XY:

0.00000447

AC XY:

AN XY:

671820

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

29156

American (AMR)

AF:

0.00

AC:

AN:

34044

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24610

East Asian (EAS)

AF:

0.00

AC:

AN:

33064

South Asian (SAS)

AF:

0.0000259

AC:

AN:

77090

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4256

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1069898

Other (OTH)

AF:

0.0000176

AC:

AN:

56928

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0662318), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.13

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.55

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.56

M_CAP

Benign

0.059

MetaRNN

Benign

0.096

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

1.8

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.020

REVEL

Benign

0.017

Sift

Benign

0.052

Sift4G

Benign

0.16

Polyphen

0.036

Vest4

0.17

MutPred

0.17

Gain of phosphorylation at P10 (P = 0.0083)

MVP

0.36

MPC

0.73

ClinPred

0.31

GERP RS

1.9

PromoterAI

0.032

Neutral

(source)

Varity_R

0.081

gMVP

0.25

Mutation Taster

=95/5

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over