4-102598208-G-C

Position:

• chr4-102598208-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003998.4(NFKB1):​c.1637+547G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.321 in 152,002 control chromosomes in the GnomAD database, including 8,163 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.32 (8163 hom., cov: 32)
• Consequence: NFKB1 NM_003998.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.375

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]

LOC105377347 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.412 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFKB1	NM_003998.4	c.1637+547G>C		intron_variant		ENST00000226574.9
LOC105377347	XR_001741780.2	n.1773C>G		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFKB1	ENST00000226574.9	c.1637+547G>C		intron_variant		1	NM_003998.4	P4

Frequencies

GnomAD3 genomes AF: 0.321 AC: 48744 AN: 151882 Hom.: 8136 Cov.: 32

Gnomad AFR AF: 0.280

Gnomad AMI AF: 0.271

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.426

Gnomad SAS AF: 0.284

Gnomad FIN AF: 0.358

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.301

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.321 AC: 48808 AN: 152002 Hom.: 8163 Cov.: 32 AF XY: 0.326 AC XY: 24232 AN XY: 74288

Gnomad4 AFR AF: 0.281

Gnomad4 AMR AF: 0.414

Gnomad4 ASJ AF: 0.293

Gnomad4 EAS AF: 0.427

Gnomad4 SAS AF: 0.283

Gnomad4 FIN AF: 0.358

Gnomad4 NFE AF: 0.317

Gnomad4 OTH AF: 0.297

Alfa AF: 0.193 Hom.: 397

Bravo AF: 0.326

Asia WGS AF: 0.373 AC: 1295 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.6
DANN	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs3774963; hg19: chr4-103519365;