chr4-102537668-A-G

Position:

• chr4-102537668-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003998.4(NFKB1):​c.160-190A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.602 in 467,118 control chromosomes in the GnomAD database, including 86,015 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (26379 hom., cov: 31)
  • Exomes 𝑓: 0.61 (59636 hom.)
• Consequence: NFKB1 NM_003998.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.282

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 4-102537668-A-G is Benign according to our data. Variant chr4-102537668-A-G is described in ClinVar as [Benign]. Clinvar id is 1290273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.676 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFKB1	NM_003998.4	c.160-190A>G		intron_variant		ENST00000226574.9	NP_003989.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFKB1	ENST00000226574.9	c.160-190A>G		intron_variant		1	NM_003998.4	ENSP00000226574	P4

Frequencies

GnomAD3 genomes AF: 0.587 AC: 89188 AN: 151838 Hom.: 26369 Cov.: 31

Gnomad AFR AF: 0.583

Gnomad AMI AF: 0.632

Gnomad AMR AF: 0.520

Gnomad ASJ AF: 0.662

Gnomad EAS AF: 0.526

Gnomad SAS AF: 0.696

Gnomad FIN AF: 0.548

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.603

Gnomad OTH AF: 0.607

GnomAD4 exome AF: 0.610 AC: 192208 AN: 315162 Hom.: 59636 Cov.: 3 AF XY: 0.615 AC XY: 103247 AN XY: 167770

Gnomad4 AFR exome AF: 0.593

Gnomad4 AMR exome AF: 0.473

Gnomad4 ASJ exome AF: 0.662

Gnomad4 EAS exome AF: 0.579

Gnomad4 SAS exome AF: 0.708

Gnomad4 FIN exome AF: 0.577

Gnomad4 NFE exome AF: 0.608

Gnomad4 OTH exome AF: 0.595

GnomAD4 genome AF: 0.587 AC: 89222 AN: 151956 Hom.: 26379 Cov.: 31 AF XY: 0.585 AC XY: 43428 AN XY: 74258

Gnomad4 AFR AF: 0.582

Gnomad4 AMR AF: 0.519

Gnomad4 ASJ AF: 0.662

Gnomad4 EAS AF: 0.526

Gnomad4 SAS AF: 0.696

Gnomad4 FIN AF: 0.548

Gnomad4 NFE AF: 0.603

Gnomad4 OTH AF: 0.611

Alfa AF: 0.603 Hom.: 15238

Bravo AF: 0.581

Asia WGS AF: 0.582 AC: 2026 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.3
DANN	Benign	0.66

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: rs230526; hg19: chr4-103458825;