Genetic Variant NFKBIL1:c.-13+590T>G (chr6-31547563-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001144962.2(NFKBIL1):c.-13+590T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000245 in 407,800 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 29)

Exomes 𝑓: 0.0000025 ( 0 hom. )

Consequence

NFKBIL1
NM_001144962.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.27

Publications

59 publications found

Variant links:

Genes affected

NFKBIL1 (HGNC:7800): (NFKB inhibitor like 1) This gene encodes a divergent member of the I-kappa-B family of proteins. Its function has not been determined. The gene lies within the major histocompatibility complex (MHC) class I region on chromosome 6. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2009]

NFKBIL1 links:

ATP6V1G2 (HGNC:862): (ATPase H+ transporting V1 subunit G2) This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of intracellular compartments of eukaryotic cells. V-ATPase dependent acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain. The V1 domain consists of three A and three B subunits, two G subunits plus the C, D, E, F, and H subunits. The V1 domain contains the ATP catalytic site. The V0 domain consists of five different subunits: a, c, c', c'', and d. Additional isoforms of many of the V1 and V0 subunit proteins are encoded by multiple genes or alternatively spliced transcript variants. This encoded protein is one of three V1 domain G subunit proteins. This gene had previous gene symbols of ATP6G and ATP6G2. Alternatively spliced transcript variants encoding different isoforms have been described. Read-through transcription also exists between this gene and the downstream DEAD (Asp-Glu-Ala-Asp) box polypeptide 39B (DDX39B) gene. [provided by RefSeq, Feb 2011]

ATP6V1G2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.03).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
NFKBIL1	NM_001144962.2 link	c.-13+590T>G	intron_variant	Intron 1 of 3		NP_001138434.1
NFKBIL1	NM_001144963.2 link	c.-13+590T>G	intron_variant	Intron 1 of 3		NP_001138435.1
NFKBIL1	NM_005007.4 link	c.-132T>G	upstream_gene_variant		ENST00000376148.9	NP_004998.3
NFKBIL1	NM_001144961.2 link	c.-132T>G	upstream_gene_variant			NP_001138433.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFKBIL1	ENST00000376148.9 link	c.-132T>G		upstream_gene_variant		1	NM_005007.4	ENSP00000365318.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000245

AC:

AN:

407800

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

215200

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

9704

American (AMR)

AF:

0.00

AC:

AN:

13586

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12320

East Asian (EAS)

AF:

0.00

AC:

AN:

26734

South Asian (SAS)

AF:

0.00

AC:

AN:

34660

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28862

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1852

European-Non Finnish (NFE)

AF:

0.00000390

AC:

AN:

256554

Other (OTH)

AF:

0.00

AC:

AN:

23528

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

8.0

(source)

DANN

Benign

0.47

PhyloP100

1.3

PromoterAI

0.31

Neutral

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over