11-65654452-G-A

Variant names:

• chr11-65654452-G-A
• rs201037601
• NM_021975.4:c.1582C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_021975.4(RELA):​c.1582C>T​(p.Leu528Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000844 in 1,456,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L528I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000084 (0 hom.)
• Consequence: RELA NM_021975.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.74
• Publications: 2 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14324412).
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000844 (123/1456798) while in subpopulation NFE AF = 0.000109 (121/1110052). AF 95% confidence interval is 0.0000931. There are 0 homozygotes in GnomAdExome4. There are 64 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 123 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RELA	NM_021975.4	c.1582C>T	p.Leu528Phe	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.1582C>T	p.Leu528Phe	missense_variant	Exon 11 of 11	1	NM_021975.4	ENSP00000384273.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000409 AC: 1 AN: 244246 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: 0.00000901

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000844 AC: 123 AN: 1456798 Hom.: 0 Cov.: 31 AF XY: 0.0000883 AC XY: 64 AN XY: 724600

African (AFR) AF: 0.00 AC: 0 AN: 33116

American (AMR) AF: 0.00 AC: 0 AN: 43474

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25828

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.00 AC: 0 AN: 85540

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.000109 AC: 121 AN: 1110052

Other (OTH) AF: 0.0000333 AC: 2 AN: 60100

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 528 of the RELA protein (p.Leu528Phe). This variant is present in population databases (rs201037601, gnomAD 0.002%). 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 (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	0.080
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T;T;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.;.
PhyloP100		2.7
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.32	N;.;N
REVEL	Benign	0.070
Sift	Benign	0.24	T;.;T
Sift4G	Benign	0.40	T;T;T
Polyphen		0.84	P;.;P
Vest4		0.22
MutPred		0.14		Gain of catalytic residue at L528 (P = 0.0753);.;.;
MVP		0.55
MPC		1.4
ClinPred		0.32	T
GERP RS		1.1
Varity_R		0.13
gMVP		0.098
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201037601; hg19: chr11-65421923; COSMIC: COSV100425911; COSMIC: COSV100425911;