NM_003998.4:c.10G>A

Variant names:

• chr4-102525528-G-A
• rs1740854197
• NM_003998.4:c.10G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_003998.4(NFKB1):​c.10G>A​(p.Asp4Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,170 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: NFKB1 NM_003998.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.83

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 -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKB1	NM_003998.4	c.10G>A	p.Asp4Asn	missense_variant	Exon 2 of 24	ENST00000226574.9	NP_003989.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFKB1	ENST00000226574.9	c.10G>A	p.Asp4Asn	missense_variant	Exon 2 of 24	1	NM_003998.4	ENSP00000226574.4
NFKB1	ENST00000505458.5	c.10G>A	p.Asp4Asn	missense_variant	Exon 2 of 24	1		ENSP00000424790.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461170 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726910

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000895

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: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 4 of the NFKB1 protein (p.Asp4Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NFKB1-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 tolerated. 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	0.11
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	.;T;.;.;T;T
Eigen	Benign	0.036
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.74	T;.;T;T;T;T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.14	T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.8	L;L;.;.;L;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.85	N;N;N;N;N;N
REVEL	Benign	0.078
Sift	Uncertain	0.0060	D;D;D;D;D;D
Sift4G	Uncertain	0.034	D;D;D;D;D;D
Polyphen		0.59	P;P;.;.;P;.
Vest4		0.16
MutPred		0.20		Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);.;.;Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);
MVP		0.69
MPC		1.0
ClinPred		0.78	D
GERP RS		4.3
Varity_R		0.093
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.27		Position offset: -16

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1740854197; hg19: chr4-103446685;