rs728440

Variant names:

• chr4-102531105-G-A
• rs728440
• NM_003998.4:c.118+1191G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-102531105-G-A
• chr4-102531105-G-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_003998.4(NFKB1):​c.118+1191G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0178 in 152,216 control chromosomes in the GnomAD database, including 39 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 0.018 (39 hom., cov: 32)
• Consequence: NFKB1 NM_003998.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0940
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0178 (2704/152216) while in subpopulation AFR AF = 0.045 (1867/41514). AF 95% confidence interval is 0.0433. There are 39 homozygotes in GnomAd4. There are 1291 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2704 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKB1	NM_003998.4	MANE Select	c.118+1191G>A		intron	N/A	NP_003989.2
	NFKB1	NM_001382625.1		c.118+1191G>A		intron	N/A	NP_001369554.1
	NFKB1	NM_001382626.1		c.118+1191G>A		intron	N/A	NP_001369555.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKB1	ENST00000226574.9	TSL:1 MANE Select	c.118+1191G>A		intron	N/A	ENSP00000226574.4
	NFKB1	ENST00000394820.8	TSL:1	c.118+1191G>A		intron	N/A	ENSP00000378297.4
	NFKB1	ENST00000505458.5	TSL:1	c.118+1191G>A		intron	N/A	ENSP00000424790.1

Frequencies

GnomAD3 genomes AF: 0.0178 AC: 2704 AN: 152098 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.0451

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00596

Gnomad ASJ AF: 0.00835

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.0126

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00797

Gnomad OTH AF: 0.0115

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

GnomAD4 genome AF: 0.0178 AC: 2704 AN: 152216 Hom.: 39 Cov.: 32 AF XY: 0.0173 AC XY: 1291 AN XY: 74422

African (AFR) AF: 0.0450 AC: 1867 AN: 41514

American (AMR) AF: 0.00595 AC: 91 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00835 AC: 29 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4824

European-Finnish (FIN) AF: 0.0126 AC: 134 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00798 AC: 543 AN: 68008

Other (OTH) AF: 0.0114 AC: 24 AN: 2112

Alfa AF: 0.00778 Hom.: 2

Bravo AF: 0.0181

Asia WGS AF: 0.00231 AC: 10 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.56
DANN	Benign	0.50
PhyloP100		0.094
Mutation Taster		=100/0	polymorphism

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: rs728440; hg19: chr4-103452262;