chr19-45001580-A-G

Position:

• chr19-45001580-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_006509.4(RELB):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RELB NM_006509.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.488

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RELB	NM_006509.4	c.1A>G	p.Met1?	start_lost	1/12	ENST00000221452.13
RELB	NM_001411087.1	c.1A>G	p.Met1?	start_lost	1/11
RELB	XM_005259128.3	c.1A>G	p.Met1?	start_lost	1/11
RELB	XM_047439189.1	c.-464A>G		5_prime_UTR_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RELB	ENST00000221452.13	c.1A>G	p.Met1?	start_lost	1/12	1	NM_006509.4	P2
RELB	ENST00000505236.2	c.1A>G	p.Met1?	start_lost	1/11	5		A2
RELB	ENST00000509480.5	c.1A>G	p.Met1?	start_lost, NMD_transcript_variant	1/5	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1305368 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 642730

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: 0.00

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 03, 2021

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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals with RELB-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change affects the initiator methionine of the RELB mRNA. The next in-frame methionine is located at codon 18. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	12
DANN	Benign	0.93
DEOGEN2	Benign	0.13	T;T;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.90	.;D;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.67	D;D;D
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PROVEAN	Benign	-0.11	N;.;N
REVEL	Benign	0.11
Sift	Benign	0.71	T;.;T
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.0	.;.;B
Vest4		0.15
MutPred		0.99		Loss of methylation at R3 (P = 0.0913);Loss of methylation at R3 (P = 0.0913);Loss of methylation at R3 (P = 0.0913);
MVP		0.35
ClinPred		0.063	T
GERP RS		-0.96
Varity_R		0.10
gMVP		0.30

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-45504838;