4-102525537-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_003998.4(NFKB1):c.19T>C(p.Tyr7His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,126 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (1 hom.)
• Consequence: NFKB1 NM_003998.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.43

Genes affected

NFKB1 (HGNC:7794): (nuclear factor kappa B subunit 1) This gene encodes a 105 kD protein which can undergo cotranslational processing by the 26S proteasome to produce a 50 kD protein. The 105 kD protein is a Rel protein-specific transcription inhibitor and the 50 kD protein is a DNA binding subunit of the NF-kappa-B (NFKB) protein complex. NFKB is a transcription regulator that is activated by various intra- and extra-cellular stimuli such as cytokines, oxidant-free radicals, ultraviolet irradiation, and bacterial or viral products. Activated NFKB translocates into the nucleus and stimulates the expression of genes involved in a wide variety of biological functions. Inappropriate activation of NFKB has been associated with a number of inflammatory diseases while persistent inhibition of NFKB leads to inappropriate immune cell development or delayed cell growth. NFKB is a critical regulator of the immediate-early response to viral infection. Alternative splicing results in multiple transcript variants encoding different isoforms, at least one of which is proteolytically processed. [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, NFKB1
• BP4: Computational evidence support a benign effect (MetaRNN=0.1928846).
• BS2: High AC in GnomAdExome at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFKB1	NM_003998.4	c.19T>C	p.Tyr7His	missense_variant	2/24	ENST00000226574.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFKB1	ENST00000226574.9	c.19T>C	p.Tyr7His	missense_variant	2/24	1	NM_003998.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 250950 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135634

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 SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461126 Hom.: 1 Cov.: 30 AF XY: 0.00000825 AC XY: 6 AN XY: 726886

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: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 09, 2022

This variant is present in population databases (rs764715465, gnomAD 0.02%). This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 7 of the NFKB1 protein (p.Tyr7His). This variant has not been reported in the literature in individuals affected with NFKB1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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	0.25
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.33
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.79	T;.;T;T;T;T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.19	T;T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.8	L;L;.;.;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-0.72	N;N;N;N;N;N
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;T;D;D;T;D
Polyphen		1.0	D;D;.;.;D;.
Vest4		0.40
MutPred		0.23		Loss of phosphorylation at Y7 (P = 0.0098);Loss of phosphorylation at Y7 (P = 0.0098);.;.;Loss of phosphorylation at Y7 (P = 0.0098);Loss of phosphorylation at Y7 (P = 0.0098);
MVP		0.60
MPC		2.5
ClinPred		0.56	D
GERP RS		5.1
Varity_R		0.42
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs764715465; hg19: chr4-103446694;