4-102529836-A-T

Position:

• chr4-102529836-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_003998.4(NFKB1):​c.40A>T​(p.Met14Leu) variant causes a missense, splice region 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. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NFKB1 NM_003998.4 missense, splice_region
• Scores: Splicing: ADA: 0.1954
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.45

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NFKB1. . Gene score misZ 3.1933 (greater than the threshold 3.09). Trascript score misZ 3.9653 (greater than threshold 3.09). GenCC has associacion of gene with immunodeficiency, common variable, 12, common variable immunodeficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.15527835).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFKB1	NM_003998.4	c.40A>T	p.Met14Leu	missense_variant, splice_region_variant	3/24	ENST00000226574.9	NP_003989.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFKB1	ENST00000226574.9	c.40A>T	p.Met14Leu	missense_variant, splice_region_variant	3/24	1	NM_003998.4	ENSP00000226574.4
NFKB1	ENST00000505458.5	c.40A>T	p.Met14Leu	missense_variant, splice_region_variant	3/24	1		ENSP00000424790.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.40A>T (p.M14L) alteration is located in exon 3 (coding exon 2) of the NFKB1 gene. This alteration results from a A to T substitution at nucleotide position 40, causing the methionine (M) at amino acid position 14 to be replaced by a leucine (L). 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	Benign	0.082
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.20	.;T;.;.;T;T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.040
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.64	T;.;T;T;T;T
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.16	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;L;.;.;L;.
MutationTaster	Benign	0.96	D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.68	N;N;N;N;N;N
REVEL	Benign	0.085
Sift	Pathogenic	0.0	D;D;D;D;D;T
Sift4G	Benign	0.31	T;T;T;T;T;T
Polyphen		0.0080	B;B;.;.;B;.
Vest4		0.25
MutPred		0.25		Loss of disorder (P = 0.1009);Loss of disorder (P = 0.1009);.;.;Loss of disorder (P = 0.1009);Loss of disorder (P = 0.1009);
MVP		0.59
MPC		0.96
ClinPred		0.58	D
GERP RS		5.0
Varity_R		0.24
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.20
dbscSNV1_RF	Benign	0.49
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-103450993;