chr19-45001685-G-A

Position:

chr19-45001685-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_006509.4(RELB):c.106G>A(p.Gly36Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000075 in 1,519,178 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G36E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000076 ( 0 hom. )

Consequence

RELB
NM_006509.4 missense, splice_region

Scores

Splicing: ADA: 0.9993

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.72

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
RELB	NM_006509.4 linkuse as main transcript	c.106G>A	p.Gly36Arg	missense_variant, splice_region_variant	1/12	ENST00000221452.13
RELB	NM_001411087.1 linkuse as main transcript	c.106G>A	p.Gly36Arg	missense_variant, splice_region_variant	1/11
RELB	XM_005259128.3 linkuse as main transcript	c.106G>A	p.Gly36Arg	missense_variant, splice_region_variant	1/11
RELB	XM_047439189.1 linkuse as main transcript	c.-359G>A		splice_region_variant, 5_prime_UTR_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
RELB	ENST00000221452.13 linkuse as main transcript	c.106G>A	p.Gly36Arg	missense_variant, splice_region_variant	1/12	1	NM_006509.4	P2
RELB	ENST00000505236.2 linkuse as main transcript	c.106G>A	p.Gly36Arg	missense_variant, splice_region_variant	1/11	5		A2
RELB	ENST00000509480.5 linkuse as main transcript	c.106G>A	p.Gly36Arg	missense_variant, splice_region_variant, NMD_transcript_variant	1/5	3

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000509

AC:

AN:

117946

Hom.:

AF XY:

0.0000154

AC XY:

AN XY:

64972

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000135

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000761

AC:

104

AN:

1367032

Hom.:

Cov.:

AF XY:

0.0000653

AC XY:

AN XY:

674152

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000300

Gnomad4 NFE exome

AF:

0.0000925

Gnomad4 OTH exome

AF:

0.0000699

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000831

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

RELB-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 13, 2022

The RELB c.106G>A variant is predicted to result in the amino acid substitution p.Gly36Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-45504943-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 36 of the RELB protein (p.Gly36Arg). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with RELB-related conditions. ClinVar contains an entry for this variant (Variation ID: 1413689). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.32

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;T;.

Eigen

Benign

0.13

Eigen_PC

Benign

0.083

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.77

.;T;T

M_CAP

Uncertain

0.26

MetaRNN

Uncertain

0.43

T;T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.69

N;N;.

MutationTaster

Benign

0.85

D;D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.64

N;.;N

REVEL

Benign

0.16

Sift

Uncertain

0.0040

D;.;D

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

0.99

.;.;D

Vest4

0.50

MutPred

0.14

Gain of solvent accessibility (P = 0.0584);Gain of solvent accessibility (P = 0.0584);Gain of solvent accessibility (P = 0.0584);

MVP

0.54

MPC

1.7

ClinPred

0.34

GERP RS

3.1

Varity_R

0.25

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.96

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

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