chr4-102529852-C-T

Variant names:

• chr4-102529852-C-T
• rs750825184
• NM_003998.4:c.56C>T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003998.4(NFKB1):​c.56C>T​(p.Pro19Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000255 in 1,453,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: NFKB1 NM_003998.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.352

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.031309366).
• BP6: Variant 4-102529852-C-T is Benign according to our data. Variant chr4-102529852-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2281313.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000255 (37/1453044) while in subpopulation SAS AF= 0.000409 (35/85490). AF 95% confidence interval is 0.000302. There are 0 homozygotes in gnomad4_exome. There are 24 alleles in male gnomad4_exome subpopulation. Median coverage is 28. This position pass quality control queck.
• BS2: High AC in GnomAdExome4 at 37 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKB1	NM_003998.4	c.56C>T	p.Pro19Leu	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.56C>T	p.Pro19Leu	missense_variant	Exon 3 of 24	1	NM_003998.4	ENSP00000226574.4
NFKB1	ENST00000505458.5	c.56C>T	p.Pro19Leu	missense_variant	Exon 3 of 24	1		ENSP00000424790.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000609 AC: 15 AN: 246124 Hom.: 0 AF XY: 0.0000676 AC XY: 9 AN XY: 133102

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: 0.000501

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000255 AC: 37 AN: 1453044 Hom.: 0 Cov.: 28 AF XY: 0.0000332 AC XY: 24 AN XY: 723108

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: 0.000409

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.04e-7

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000577 AC: 7

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Apr 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.56C>T (p.P19L) alteration is located in exon 3 (coding exon 2) of the NFKB1 gene. This alteration results from a C to T substitution at nucleotide position 56, causing the proline (P) at amino acid position 19 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NFKB1: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	13
DANN	Benign	0.81
DEOGEN2	Benign	0.25	.;T;.;.;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.58	T;.;T;T;T;T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.031	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N;.;.;N;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.0	N;N;N;N;N;N
REVEL	Benign	0.039
Sift	Benign	0.030	D;T;T;D;T;D
Sift4G	Benign	0.30	T;T;T;T;T;T
Polyphen		0.043	B;B;.;.;B;.
Vest4		0.17
MutPred		0.32		Loss of disorder (P = 0.0299);Loss of disorder (P = 0.0299);.;.;Loss of disorder (P = 0.0299);Loss of disorder (P = 0.0299);
MVP		0.42
MPC		1.2
ClinPred		0.047	T
GERP RS		-0.53
Varity_R		0.041
gMVP		0.38

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

Publications

LitVar

Other links and lift over

dbSNP: rs750825184; hg19: chr4-103451009;