Variant 19-45001626-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_006509.4(RELB):c.47G>C(p.Arg16Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 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. R16W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000015 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

RELB
NM_006509.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.750

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a modified_residue Omega-N-methylarginine (size 0) in uniprot entity RELB_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.124610156).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
RELB	NM_006509.4 linkuse as main transcript	c.47G>C	p.Arg16Pro	missense_variant	1/12	ENST00000221452.13
RELB	NM_001411087.1 linkuse as main transcript	c.47G>C	p.Arg16Pro	missense_variant	1/11
RELB	XM_005259128.3 linkuse as main transcript	c.47G>C	p.Arg16Pro	missense_variant	1/11
RELB	XM_047439189.1 linkuse as main transcript	c.-418G>C		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.47G>C	p.Arg16Pro	missense_variant	1/12	1	NM_006509.4	P2
RELB	ENST00000505236.2 linkuse as main transcript	c.47G>C	p.Arg16Pro	missense_variant	1/11	5		A2
RELB	ENST00000509480.5 linkuse as main transcript	c.47G>C	p.Arg16Pro	missense_variant, NMD_transcript_variant	1/5	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000146

AC:

AN:

1370200

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

675714

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:

0.0000257

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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 01, 2023

The c.47G>C (p.R16P) alteration is located in exon 1 (coding exon 1) of the RELB gene. This alteration results from a G to C substitution at nucleotide position 47, causing the arginine (R) at amino acid position 16 to be replaced by a proline (P). 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

Benign

0.15

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

T;T;.

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.55

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.54

.;T;T

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

N;N;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.68

N;.;N

REVEL

Benign

0.063

Sift

Benign

0.12

T;.;T

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.0

.;.;B

Vest4

0.16

MutPred

0.21

Loss of MoRF binding (P = 0.0012);Loss of MoRF binding (P = 0.0012);Loss of MoRF binding (P = 0.0012);

MVP

0.61

MPC

0.92

ClinPred

0.80

GERP RS

0.79

Varity_R

0.28

gMVP

0.38

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

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