chr4-102606719-T-C

Variant names:

• chr4-102606719-T-C
• rs4648095
• NM_003998.4:c.1954+22T>C

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.1954+22T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0457 in 1,601,214 control chromosomes in the GnomAD database, including 1,810 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (282 hom., cov: 32)
  • Exomes 𝑓: 0.045 (1528 hom.)
• Consequence: NFKB1 NM_003998.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.505
• Publications: 19 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

ENSG00000304360 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 4-102606719-T-C is Benign according to our data. Variant chr4-102606719-T-C is described in CliVar as Benign. Clinvar id is 1289420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102606719-T-C is described in CliVar as Benign. Clinvar id is 1289420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102606719-T-C is described in CliVar as Benign. Clinvar id is 1289420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102606719-T-C is described in CliVar as Benign. Clinvar id is 1289420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102606719-T-C is described in CliVar as Benign. Clinvar id is 1289420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102606719-T-C is described in CliVar as Benign. Clinvar id is 1289420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102606719-T-C is described in CliVar as Benign. Clinvar id is 1289420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102606719-T-C is described in CliVar as Benign. Clinvar id is 1289420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102606719-T-C is described in CliVar as Benign. Clinvar id is 1289420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102606719-T-C is described in CliVar as Benign. Clinvar id is 1289420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102606719-T-C is described in CliVar as Benign. Clinvar id is 1289420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102606719-T-C is described in CliVar as Benign. Clinvar id is 1289420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102606719-T-C is described in CliVar as Benign. Clinvar id is 1289420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102606719-T-C is described in CliVar as Benign. Clinvar id is 1289420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102606719-T-C is described in CliVar as Benign. Clinvar id is 1289420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102606719-T-C is described in CliVar as Benign. Clinvar id is 1289420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102606719-T-C is described in CliVar as Benign. Clinvar id is 1289420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102606719-T-C is described in CliVar as Benign. Clinvar id is 1289420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102606719-T-C is described in CliVar as Benign. Clinvar id is 1289420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102606719-T-C is described in CliVar as Benign. Clinvar id is 1289420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102606719-T-C is described in CliVar as Benign. Clinvar id is 1289420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102606719-T-C is described in CliVar as Benign. Clinvar id is 1289420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102606719-T-C is described in CliVar as Benign. Clinvar id is 1289420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102606719-T-C is described in CliVar as Benign. Clinvar id is 1289420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102606719-T-C is described in CliVar as Benign. Clinvar id is 1289420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102606719-T-C is described in CliVar as Benign. Clinvar id is 1289420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102606719-T-C is described in CliVar as Benign. Clinvar id is 1289420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102606719-T-C is described in CliVar as Benign. Clinvar id is 1289420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102606719-T-C is described in CliVar as Benign. Clinvar id is 1289420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0863 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKB1	NM_003998.4	c.1954+22T>C		intron_variant	Intron 17 of 23	ENST00000226574.9	NP_003989.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFKB1	ENST00000226574.9	c.1954+22T>C		intron_variant	Intron 17 of 23	1	NM_003998.4	ENSP00000226574.4
NFKB1	ENST00000505458.5	c.1951+22T>C		intron_variant	Intron 17 of 23	1		ENSP00000424790.1

Frequencies

GnomAD3 genomes AF: 0.0571 AC: 8688 AN: 152160 Hom.: 282 Cov.: 32

Gnomad AFR AF: 0.0887

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.0351

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.0630

Gnomad SAS AF: 0.0346

Gnomad FIN AF: 0.0655

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0452

Gnomad OTH AF: 0.0478

GnomAD2 exomes AF: 0.0460 AC: 10932 AN: 237908 AF XY: 0.0451

Gnomad AFR exome AF: 0.0902

Gnomad AMR exome AF: 0.0185

Gnomad ASJ exome AF: 0.0122

Gnomad EAS exome AF: 0.0778

Gnomad FIN exome AF: 0.0625

Gnomad NFE exome AF: 0.0474

Gnomad OTH exome AF: 0.0409

GnomAD4 exome AF: 0.0445 AC: 64487 AN: 1448936 Hom.: 1528 Cov.: 30 AF XY: 0.0441 AC XY: 31763 AN XY: 719584

African (AFR) AF: 0.0939 AC: 3124 AN: 33258

American (AMR) AF: 0.0200 AC: 873 AN: 43566

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 298 AN: 25926

East Asian (EAS) AF: 0.0586 AC: 2312 AN: 39452

South Asian (SAS) AF: 0.0290 AC: 2477 AN: 85468

European-Finnish (FIN) AF: 0.0620 AC: 3293 AN: 53120

Middle Eastern (MID) AF: 0.0249 AC: 143 AN: 5750

European-Non Finnish (NFE) AF: 0.0447 AC: 49270 AN: 1102490

Other (OTH) AF: 0.0450 AC: 2697 AN: 59906

GnomAD4 genome AF: 0.0571 AC: 8701 AN: 152278 Hom.: 282 Cov.: 32 AF XY: 0.0570 AC XY: 4245 AN XY: 74450

African (AFR) AF: 0.0887 AC: 3686 AN: 41550

American (AMR) AF: 0.0350 AC: 536 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3472

East Asian (EAS) AF: 0.0625 AC: 324 AN: 5180

South Asian (SAS) AF: 0.0353 AC: 170 AN: 4822

European-Finnish (FIN) AF: 0.0655 AC: 695 AN: 10612

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0453 AC: 3078 AN: 68020

Other (OTH) AF: 0.0473 AC: 100 AN: 2116

Alfa AF: 0.0460 Hom.: 29

Bravo AF: 0.0571

Asia WGS AF: 0.0500 AC: 173 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

- -

-

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	-0.90
CADD	Benign	0.073
DANN	Benign	0.57
PhyloP100		0.51
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: rs4648095; hg19: chr4-103527876; COSMIC: COSV56955265;