Genetic Variant RELB:p.Pro26Gln (chr19-45001656-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006509.4(RELB):c.77C>A(p.Pro26Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000073 in 1,370,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P26L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

RELB
NM_006509.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.751

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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.056124747).

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.77C>A	p.Pro26Gln	missense	Exon 1 of 12	NP_006500.2
	RELB	NM_001411087.1		c.77C>A	p.Pro26Gln	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.77C>A	p.Pro26Gln	missense	Exon 1 of 12	ENSP00000221452.7	Q01201
RELB	ENST00000505236.2	TSL:5	c.77C>A	p.Pro26Gln	missense	Exon 1 of 11	ENSP00000423287.1	D6R992
RELB	ENST00000509480.5	TSL:3	n.77C>A		non_coding_transcript_exon	Exon 1 of 5	ENSP00000427348.1	D6RIV7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.30e-7

AC:

AN:

1370470

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

675802

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30294

American (AMR)

AF:

0.00

AC:

AN:

34752

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24834

East Asian (EAS)

AF:

0.00

AC:

AN:

34138

South Asian (SAS)

AF:

0.00

AC:

AN:

77758

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33450

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4672

European-Non Finnish (NFE)

AF:

9.32e-7

AC:

AN:

1073274

Other (OTH)

AF:

0.00

AC:

AN:

57298

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.55

M_CAP

Benign

0.044

MetaRNN

Benign

0.056

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

0.75

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.090

REVEL

Benign

0.0080

Sift

Benign

0.11

Sift4G

Benign

0.097

Polyphen

0.016

Vest4

0.14

MutPred

0.20

Loss of catalytic residue at P26 (P = 0.0059)

MVP

0.28

MPC

0.54

ClinPred

0.16

GERP RS

0.68

PromoterAI

-0.063

Neutral

(source)

Varity_R

0.042

gMVP

0.12

Mutation Taster

=96/4

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over