NM_003998.4:c.53A>T

Variant names:

• chr4-102529849-A-T
• rs1364913100
• NM_003998.4:c.53A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003998.4(NFKB1):​c.53A>T​(p.Asp18Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D18A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NFKB1 NM_003998.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.47
• Publications: 7 publications found

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]

NFKB1 Gene-Disease associations (from GenCC):

• immunodeficiency, common variable, 12

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• common variable immunodeficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13425201).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKB1	NM_003998.4	c.53A>T	p.Asp18Val	missense_variant	Exon 3 of 24	ENST00000226574.9	NP_003989.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFKB1	ENST00000226574.9	c.53A>T	p.Asp18Val	missense_variant	Exon 3 of 24	1	NM_003998.4	ENSP00000226574.4
NFKB1	ENST00000505458.5	c.53A>T	p.Asp18Val	missense_variant	Exon 3 of 24	1		ENSP00000424790.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.29	.;T;.;.;T;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.58	T;.;T;T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.13	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;L;.;.;L;.
PhyloP100		2.5
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.1	N;N;D;N;N;D
REVEL	Benign	0.15
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D;D
Polyphen		0.026	B;B;.;.;B;.
Vest4		0.29
MutPred		0.47		Loss of disorder (P = 0.0243);Loss of disorder (P = 0.0243);.;.;Loss of disorder (P = 0.0243);Loss of disorder (P = 0.0243);
MVP		0.70
MPC		1.7
ClinPred		0.64	D
GERP RS		3.6
Varity_R		0.13
gMVP		0.66
Mutation Taster		=94/6	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: rs1364913100; hg19: chr4-103451006;