11-65654476-C-T

Variant names:

• chr11-65654476-C-T
• rs776126630
• NM_021975.4:c.1558G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_021975.4(RELA):​c.1558G>A​(p.Ala520Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000552 in 1,449,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A520A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: RELA NM_021975.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.168
• Publications: 1 publications found

Genes affected

RELA (HGNC:9955): (RELA proto-oncogene, NF-kB subunit) NF-kappa-B is a ubiquitous transcription factor involved in several biological processes. It is held in the cytoplasm in an inactive state by specific inhibitors. Upon degradation of the inhibitor, NF-kappa-B moves to the nucleus and activates transcription of specific genes. NF-kappa-B is composed of NFKB1 or NFKB2 bound to either REL, RELA, or RELB. The most abundant form of NF-kappa-B is NFKB1 complexed with the product of this gene, RELA. Four transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

RELA Gene-Disease associations (from GenCC):

• combined immunodeficiency due to RELA haploinsufficiency

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• mucocutaneous ulceration, chronic

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary pediatric Behçet-like disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000306723 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04680705).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RELA	NM_021975.4	c.1558G>A	p.Ala520Thr	missense_variant	Exon 11 of 11	ENST00000406246.8	NP_068810.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RELA	ENST00000406246.8	c.1558G>A	p.Ala520Thr	missense_variant	Exon 11 of 11	1	NM_021975.4	ENSP00000384273.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000423 AC: 1 AN: 236520 AF XY: 0.00000775

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: 0.00000923

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000552 AC: 8 AN: 1449536 Hom.: 0 Cov.: 31 AF XY: 0.00000416 AC XY: 3 AN XY: 720890

African (AFR) AF: 0.00 AC: 0 AN: 32568

American (AMR) AF: 0.00 AC: 0 AN: 41342

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25354

East Asian (EAS) AF: 0.00 AC: 0 AN: 39598

South Asian (SAS) AF: 0.00 AC: 0 AN: 84634

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53074

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5676

European-Non Finnish (NFE) AF: 0.00000722 AC: 8 AN: 1107564

Other (OTH) AF: 0.00 AC: 0 AN: 59726

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 520 of the RELA protein (p.Ala520Thr). This variant is present in population databases (rs776126630, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with RELA-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	13
DANN	Benign	0.64
DEOGEN2	Benign	0.34	T;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.71	T;T;T
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.047	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;.;.
PhyloP100		-0.17
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-0.78	N;.;N
REVEL	Benign	0.060
Sift	Benign	0.42	T;.;T
Sift4G	Benign	0.15	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.049
MutPred		0.17		Gain of glycosylation at A520 (P = 0.002);.;.;
MVP		0.67
MPC		0.47
ClinPred		0.0086	T
GERP RS		-0.27
Varity_R		0.091
gMVP		0.15
Mutation Taster		=97/3	polymorphism

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: rs776126630; hg19: chr11-65421947; COSMIC: COSV105162159; COSMIC: COSV105162159;