19-45032733-C-T

Variant names:

• chr19-45032733-C-T
• rs745463649
• NM_006509.4:c.1191C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_006509.4(RELB):​c.1191C>T​(p.Tyr397Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,454,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RELB NM_006509.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.57
• Publications: 3 publications found

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)

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP7: Synonymous conserved (PhyloP=2.57 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RELB	NM_006509.4	c.1191C>T	p.Tyr397Tyr	synonymous_variant	Exon 9 of 12	ENST00000221452.13	NP_006500.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RELB	ENST00000221452.13	c.1191C>T	p.Tyr397Tyr	synonymous_variant	Exon 9 of 12	1	NM_006509.4	ENSP00000221452.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00 AC: 0 AN: 236078 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1454362 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 722688

African (AFR) AF: 0.0000300 AC: 1 AN: 33336

American (AMR) AF: 0.00 AC: 0 AN: 43518

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25832

East Asian (EAS) AF: 0.00 AC: 0 AN: 39436

South Asian (SAS) AF: 0.00 AC: 0 AN: 85024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52844

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108572

Other (OTH) AF: 0.00 AC: 0 AN: 60116

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	8.0
DANN	Benign	0.63
PhyloP100		2.6
PromoterAI		0.0020	Neutral

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

Other links and lift over

dbSNP: rs745463649; hg19: chr19-45535991;