19-45001580-A-G

Variant names:

• chr19-45001580-A-G
• NM_006509.4:c.1A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_Supporting 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 Uncertain_significance. Variant got 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 18 codons. Genomic position: 45001631. Lost 0.030 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RELB	NM_006509.4	c.1A>G	p.Met1?	start_lost	Exon 1 of 12	ENST00000221452.13	NP_006500.2
RELB	NM_001411087.1	c.1A>G	p.Met1?	start_lost	Exon 1 of 11		NP_001398016.1
RELB	XM_005259128.3	c.1A>G	p.Met1?	start_lost	Exon 1 of 11		XP_005259185.1
RELB	XM_047439189.1	c.-464A>G		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.1A>G	p.Met1?	start_lost	Exon 1 of 12	1	NM_006509.4	ENSP00000221452.7
RELB	ENST00000505236.2	c.1A>G	p.Met1?	start_lost	Exon 1 of 11	5		ENSP00000423287.1
RELB	ENST00000509480.5	n.1A>G		non_coding_transcript_exon_variant	Exon 1 of 5	3		ENSP00000427348.1

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

Jun 03, 2021

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. 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
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;