rs4648049

Variant names:

• chr4-102593580-C-T
• rs4648049
• NM_003998.4:c.1210+12C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003998.4(NFKB1):​c.1210+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0467 in 1,603,918 control chromosomes in the GnomAD database, including 2,046 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (406 hom., cov: 32)
  • Exomes 𝑓: 0.045 (1640 hom.)
• Consequence: NFKB1 NM_003998.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.05
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• immunodeficiency, common variable, 12

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• common variable immunodeficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 4-102593580-C-T is Benign according to our data. Variant chr4-102593580-C-T is described in ClinVar as Benign. ClinVar VariationId is 1168687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003998.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKB1	NM_003998.4	MANE Select	c.1210+12C>T		intron	N/A	NP_003989.2
	NFKB1	NM_001382625.1		c.1210+12C>T		intron	N/A	NP_001369554.1	P19838-2
	NFKB1	NM_001382626.1		c.1210+12C>T		intron	N/A	NP_001369555.1	P19838-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKB1	ENST00000226574.9	TSL:1 MANE Select	c.1210+12C>T		intron	N/A	ENSP00000226574.4	P19838-2
	NFKB1	ENST00000394820.8	TSL:1	c.1207+12C>T		intron	N/A	ENSP00000378297.4	P19838-1
	NFKB1	ENST00000505458.5	TSL:1	c.1207+12C>T		intron	N/A	ENSP00000424790.1	P19838-1

Frequencies

GnomAD3 genomes AF: 0.0651 AC: 9902 AN: 152052 Hom.: 401 Cov.: 32

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.0373

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.0504

Gnomad SAS AF: 0.0340

Gnomad FIN AF: 0.0654

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0453

Gnomad OTH AF: 0.0518

GnomAD2 exomes AF: 0.0462 AC: 11217 AN: 243016 AF XY: 0.0447

Gnomad AFR exome AF: 0.115

Gnomad AMR exome AF: 0.0198

Gnomad ASJ exome AF: 0.0119

Gnomad EAS exome AF: 0.0630

Gnomad FIN exome AF: 0.0619

Gnomad NFE exome AF: 0.0462

Gnomad OTH exome AF: 0.0413

GnomAD4 exome AF: 0.0448 AC: 65026 AN: 1451748 Hom.: 1640 Cov.: 34 AF XY: 0.0443 AC XY: 31985 AN XY: 722378

African (AFR) AF: 0.123 AC: 3999 AN: 32628

American (AMR) AF: 0.0212 AC: 908 AN: 42892

Ashkenazi Jewish (ASJ) AF: 0.0114 AC: 293 AN: 25720

East Asian (EAS) AF: 0.0517 AC: 2045 AN: 39536

South Asian (SAS) AF: 0.0280 AC: 2374 AN: 84872

European-Finnish (FIN) AF: 0.0618 AC: 3286 AN: 53164

Middle Eastern (MID) AF: 0.0258 AC: 146 AN: 5660

European-Non Finnish (NFE) AF: 0.0444 AC: 49222 AN: 1107452

Other (OTH) AF: 0.0460 AC: 2753 AN: 59824

GnomAD4 genome AF: 0.0653 AC: 9940 AN: 152170 Hom.: 406 Cov.: 32 AF XY: 0.0657 AC XY: 4887 AN XY: 74402

African (AFR) AF: 0.119 AC: 4948 AN: 41496

American (AMR) AF: 0.0372 AC: 569 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3472

East Asian (EAS) AF: 0.0500 AC: 259 AN: 5184

South Asian (SAS) AF: 0.0346 AC: 167 AN: 4824

European-Finnish (FIN) AF: 0.0654 AC: 692 AN: 10586

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0453 AC: 3083 AN: 68010

Other (OTH) AF: 0.0513 AC: 108 AN: 2106

Alfa AF: 0.0499 Hom.: 43

Bravo AF: 0.0667

Asia WGS AF: 0.0540 AC: 186 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.054
DANN	Benign	0.40
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4648049; hg19: chr4-103514737; COSMIC: COSV56956042; COSMIC: COSV56956042;