4-102510933-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_003998.4(NFKB1):c.-8+9145A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00744 in 1,285,530 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0049 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0078 (47 hom.)
• Consequence: NFKB1 NM_003998.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.405

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006662905).
• BP6: Variant 4-102510933-A-G is Benign according to our data. Variant chr4-102510933-A-G is described in ClinVar as [Benign]. Clinvar id is 1675952.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00489 (744/152282) while in subpopulation NFE AF= 0.00853 (580/68030). AF 95% confidence interval is 0.00795. There are 3 homozygotes in gnomad4. There are 346 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 744 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFKB1	NM_003998.4	c.-8+9145A>G		intron_variant		ENST00000226574.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFKB1	ENST00000226574.9	c.-8+9145A>G		intron_variant		1	NM_003998.4	P4

Frequencies

GnomAD3 genomes AF: 0.00489 AC: 744 AN: 152164 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00650

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00852

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00400 AC: 509 AN: 127208 Hom.: 1 AF XY: 0.00396 AC XY: 276 AN XY: 69774

Gnomad AFR exome AF: 0.00165

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00188

Gnomad FIN exome AF: 0.00487

Gnomad NFE exome AF: 0.00811

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00778 AC: 8817 AN: 1133248 Hom.: 47 Cov.: 29 AF XY: 0.00757 AC XY: 4207 AN XY: 556046

Gnomad4 AFR exome AF: 0.000949

Gnomad4 AMR exome AF: 0.00118

Gnomad4 ASJ exome AF: 0.000127

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00199

Gnomad4 FIN exome AF: 0.00531

Gnomad4 NFE exome AF: 0.00907

Gnomad4 OTH exome AF: 0.00491

GnomAD4 genome AF: 0.00489 AC: 744 AN: 152282 Hom.: 3 Cov.: 32 AF XY: 0.00465 AC XY: 346 AN XY: 74460

Gnomad4 AFR AF: 0.00116

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00650

Gnomad4 NFE AF: 0.00853

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00583 Hom.: 1

Bravo AF: 0.00410

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.00960 AC: 37

ExAC AF: 0.00190 AC: 28

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2023

NFKB1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	5.9
Dann	Benign	0.58
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.012	N
LIST_S2	Uncertain	0.90	D;D
MetaRNN	Benign	0.0067	T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N;N;N
PROVEAN	Benign	0.040	N;N
REVEL	Benign	0.074
Sift	Pathogenic	0.0	D;D
MVP		0.28
ClinPred		0.042	T
GERP RS		-2.4

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: rs188317269; hg19: chr4-103432090;