19-45001593-G-A

Variant names:

• chr19-45001593-G-A
• rs1413862268
• NM_006509.4:c.14G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006509.4(RELB):​c.14G>A​(p.Gly5Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000223 in 1,344,952 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: RELB NM_006509.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0280

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06950757).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RELB	NM_006509.4	c.14G>A	p.Gly5Glu	missense_variant	Exon 1 of 12	ENST00000221452.13	NP_006500.2
RELB	NM_001411087.1	c.14G>A	p.Gly5Glu	missense_variant	Exon 1 of 11		NP_001398016.1
RELB	XM_005259128.3	c.14G>A	p.Gly5Glu	missense_variant	Exon 1 of 11		XP_005259185.1
RELB	XM_047439189.1	c.-451G>A		5_prime_UTR_variant	Exon 1 of 13		XP_047295145.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RELB	ENST00000221452.13	c.14G>A	p.Gly5Glu	missense_variant	Exon 1 of 12	1	NM_006509.4	ENSP00000221452.7
RELB	ENST00000505236.2	c.14G>A	p.Gly5Glu	missense_variant	Exon 1 of 11	5		ENSP00000423287.1
RELB	ENST00000509480.5	n.14G>A		non_coding_transcript_exon_variant	Exon 1 of 5	3		ENSP00000427348.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000223 AC: 3 AN: 1344952 Hom.: 0 Cov.: 30 AF XY: 0.00000151 AC XY: 1 AN XY: 662942

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: 0.00

Gnomad4 NFE exome AF: 0.00000282

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 30, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 5 of the RELB protein (p.Gly5Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RELB-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.53	.;T;T
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.070	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.20	N;.;N
REVEL	Benign	0.025
Sift	Benign	0.14	T;.;T
Sift4G	Benign	0.66	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.10
MutPred		0.28		Loss of MoRF binding (P = 0.0028);Loss of MoRF binding (P = 0.0028);Loss of MoRF binding (P = 0.0028);
MVP		0.25
MPC		0.81
ClinPred		0.12	T
GERP RS		-0.60
Varity_R		0.042
gMVP		0.18

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

Other links and lift over

dbSNP: rs1413862268; hg19: chr19-45504851;