11-65654427-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_021975.4(RELA):c.1607C>G(p.Ser536Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. S536S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RELA NM_021975.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.94

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a modified_residue Phosphoserine; by IKKB (size 0) in uniprot entity TF65_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32439035).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RELA	NM_021975.4	c.1607C>G	p.Ser536Cys	missense_variant	11/11	ENST00000406246.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RELA	ENST00000406246.8	c.1607C>G	p.Ser536Cys	missense_variant	11/11	1	NM_021975.4	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459038 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725734

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 01, 2023

The c.1607C>G (p.S536C) alteration is located in exon 11 (coding exon 11) of the RELA gene. This alteration results from a C to G substitution at nucleotide position 1607, causing the serine (S) at amino acid position 536 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;T;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	0.55	N;.;.
MutationTaster	Benign	0.94	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.6	N;.;N
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D;.;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.59
MutPred		0.20		Loss of phosphorylation at S536 (P = 0.0167);.;.;
MVP		0.56
MPC		1.4
ClinPred		0.85	D
GERP RS		4.0
Varity_R		0.56
gMVP		0.55

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: chr11-65421898;