Genetic Variant NM_006509.4:c.89C>T (chr19-45001668-C-T) – 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.89C>T(p.Pro30Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000219 in 1,369,474 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. P30R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

RELB
NM_006509.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.283

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:

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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=0.09569931).

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.89C>T	p.Pro30Leu	missense	Exon 1 of 12	NP_006500.2
	RELB	NM_001411087.1		c.89C>T	p.Pro30Leu	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.89C>T	p.Pro30Leu	missense	Exon 1 of 12	ENSP00000221452.7	Q01201
RELB	ENST00000505236.2	TSL:5	c.89C>T	p.Pro30Leu	missense	Exon 1 of 11	ENSP00000423287.1	D6R992
RELB	ENST00000509480.5	TSL:3	n.89C>T		non_coding_transcript_exon	Exon 1 of 5	ENSP00000427348.1	D6RIV7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000219

AC:

AN:

1369474

Hom.:

Cov.:

AF XY:

0.00000296

AC XY:

AN XY:

675276

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:

30266

American (AMR)

AF:

0.00

AC:

AN:

34614

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24806

East Asian (EAS)

AF:

0.00

AC:

AN:

34064

South Asian (SAS)

AF:

0.00

AC:

AN:

77660

European-Finnish (FIN)

AF:

0.0000299

AC:

AN:

33424

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4682

European-Non Finnish (NFE)

AF:

0.00000186

AC:

AN:

1072680

Other (OTH)

AF:

0.00

AC:

AN:

57278

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0225104), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.17

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.76

M_CAP

Benign

0.078

MetaRNN

Benign

0.096

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

0.28

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.2

REVEL

Benign

0.021

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0050

Polyphen

0.30

Vest4

0.15

MutPred

0.21

Loss of glycosylation at P30 (P = 0.059)

MVP

0.38

MPC

0.59

ClinPred

0.33

GERP RS

2.1

PromoterAI

-0.068

Neutral

(source)

Varity_R

0.12

gMVP

0.24

Mutation Taster

=90/10

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

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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