19-45001607-C-A

Position:

• chr19-45001607-C-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.28C>A​(p.Pro10Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000022 in 1,362,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: Not reported in ClinVar
• Conservation: PhyloP100: 1.83

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=0.09626782).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RELB	NM_006509.4	c.28C>A	p.Pro10Thr	missense_variant	1/12	ENST00000221452.13
RELB	NM_001411087.1	c.28C>A	p.Pro10Thr	missense_variant	1/11
RELB	XM_005259128.3	c.28C>A	p.Pro10Thr	missense_variant	1/11
RELB	XM_047439189.1	c.-437C>A		5_prime_UTR_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RELB	ENST00000221452.13	c.28C>A	p.Pro10Thr	missense_variant	1/12	1	NM_006509.4	P2
RELB	ENST00000505236.2	c.28C>A	p.Pro10Thr	missense_variant	1/11	5		A2
RELB	ENST00000509480.5	c.28C>A	p.Pro10Thr	missense_variant, NMD_transcript_variant	1/5	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000220 AC: 3 AN: 1362466 Hom.: 0 Cov.: 30 AF XY: 0.00000447 AC XY: 3 AN XY: 671820

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: 0.0000259

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000176

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.13	T;T;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.55
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.096	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.020	N;.;N
REVEL	Benign	0.017
Sift	Benign	0.052	T;.;T
Sift4G	Benign	0.16	T;T;T
Polyphen		0.036	.;.;B
Vest4		0.17
MutPred		0.17		Gain of phosphorylation at P10 (P = 0.0083);Gain of phosphorylation at P10 (P = 0.0083);Gain of phosphorylation at P10 (P = 0.0083);
MVP		0.36
MPC		0.73
ClinPred		0.31	T
GERP RS		1.9
Varity_R		0.081
gMVP		0.25

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: rs936935306; hg19: chr19-45504865;