4-102593288-C-G

Variant names:

• chr4-102593288-C-G
• rs1020760
• NM_003998.4:c.1067-137C>G

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.1067-137C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.405 in 808,716 control chromosomes in the GnomAD database, including 68,296 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13248 hom., cov: 32)
  • Exomes 𝑓: 0.40 (55048 hom.)
• Consequence: NFKB1 NM_003998.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.05
• Publications: 23 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: DEFINITIVE, STRONG 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=-0.73).
• BP6: Variant 4-102593288-C-G is Benign according to our data. Variant chr4-102593288-C-G is described in ClinVar as Benign. ClinVar VariationId is 1272513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.476 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKB1	NM_003998.4	c.1067-137C>G		intron_variant	Intron 11 of 23	ENST00000226574.9	NP_003989.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFKB1	ENST00000226574.9	c.1067-137C>G		intron_variant	Intron 11 of 23	1	NM_003998.4	ENSP00000226574.4
NFKB1	ENST00000505458.5	c.1064-137C>G		intron_variant	Intron 11 of 23	1		ENSP00000424790.1

Frequencies

GnomAD3 genomes AF: 0.415 AC: 62984 AN: 151854 Hom.: 13212 Cov.: 32

Gnomad AFR AF: 0.407

Gnomad AMI AF: 0.372

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.341

Gnomad EAS AF: 0.476

Gnomad SAS AF: 0.325

Gnomad FIN AF: 0.456

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.405

Gnomad OTH AF: 0.398

GnomAD4 exome AF: 0.403 AC: 264768 AN: 656744 Hom.: 55048 Cov.: 9 AF XY: 0.398 AC XY: 136045 AN XY: 341888

African (AFR) AF: 0.394 AC: 6385 AN: 16222

American (AMR) AF: 0.555 AC: 14270 AN: 25726

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 4982 AN: 14640

East Asian (EAS) AF: 0.425 AC: 14517 AN: 34138

South Asian (SAS) AF: 0.308 AC: 14773 AN: 47978

European-Finnish (FIN) AF: 0.442 AC: 17803 AN: 40318

Middle Eastern (MID) AF: 0.312 AC: 701 AN: 2250

European-Non Finnish (NFE) AF: 0.402 AC: 178065 AN: 443314

Other (OTH) AF: 0.413 AC: 13272 AN: 32158

GnomAD4 genome AF: 0.415 AC: 63064 AN: 151972 Hom.: 13248 Cov.: 32 AF XY: 0.418 AC XY: 31050 AN XY: 74288

African (AFR) AF: 0.407 AC: 16867 AN: 41420

American (AMR) AF: 0.485 AC: 7412 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.341 AC: 1184 AN: 3470

East Asian (EAS) AF: 0.477 AC: 2466 AN: 5174

South Asian (SAS) AF: 0.324 AC: 1564 AN: 4824

European-Finnish (FIN) AF: 0.456 AC: 4808 AN: 10542

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.405 AC: 27508 AN: 67948

Other (OTH) AF: 0.393 AC: 831 AN: 2114

Alfa AF: 0.417 Hom.: 1646

Bravo AF: 0.420

Asia WGS AF: 0.425 AC: 1474 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	12
DANN	Benign	0.76
PhyloP100		1.0
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: rs1020760; hg19: chr4-103514445; COSMIC: COSV56956809;