rs11718446

Positions:

• chr3-101833709-G-A
• chr3-101833709-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000394054.6(NFKBIZ):​c.-12+4021G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 152,036 control chromosomes in the GnomAD database, including 5,174 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 0.26 (5174 hom., cov: 32)
• Consequence: NFKBIZ ENST00000394054.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.130

Genes affected

NFKBIZ (HGNC:29805): (NFKB inhibitor zeta) This gene is a member of the ankyrin-repeat family and is induced by lipopolysaccharide (LPS). The C-terminal portion of the encoded product which contains the ankyrin repeats, shares high sequence similarity with the I kappa B family of proteins. The latter are known to play a role in inflammatory responses to LPS by their interaction with NF-B proteins through ankyrin-repeat domains. Studies in mouse indicate that this gene product is one of the nuclear I kappa B proteins and an activator of IL-6 production. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

NXPE3 (HGNC:28238): (neurexophilin and PC-esterase domain family member 3) This gene encodes a member of the neurexophilin family of neuropeptide-like glycoproteins. The encoded protein contains a variable N-terminal domain, a highly conserved neurexophilin and PC-esterase (NXPE) central domain, a short linker region, and a cysteine-rich C-terminal domain. This protein binds alpha neurexins, a group of presynaptic transmembrane receptors that promote adhesion between dendrites and axons. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2017]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFKBIZ	NM_001005474.3	c.-12+4021G>A		intron_variant			NP_001005474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFKBIZ	ENST00000394054.6	c.-12+4021G>A		intron_variant		1		ENSP00000377618	A2
NFKBIZ	ENST00000461724.5	c.-738+4021G>A		intron_variant		5		ENSP00000418502
NFKBIZ	ENST00000483180.5	c.-12+5525G>A		intron_variant		5		ENSP00000419800
NXPE3	ENST00000705586.1	c.1270-9442G>A		intron_variant				ENSP00000516140

Frequencies

GnomAD3 genomes AF: 0.257 AC: 39043 AN: 151918 Hom.: 5178 Cov.: 32

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.313

Gnomad EAS AF: 0.283

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.315

Gnomad MID AF: 0.226

Gnomad NFE AF: 0.276

Gnomad OTH AF: 0.256

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

GnomAD4 genome AF: 0.257 AC: 39043 AN: 152036 Hom.: 5174 Cov.: 32 AF XY: 0.258 AC XY: 19173 AN XY: 74304

Gnomad4 AFR AF: 0.219

Gnomad4 AMR AF: 0.235

Gnomad4 ASJ AF: 0.313

Gnomad4 EAS AF: 0.283

Gnomad4 SAS AF: 0.199

Gnomad4 FIN AF: 0.315

Gnomad4 NFE AF: 0.276

Gnomad4 OTH AF: 0.254

Alfa AF: 0.269 Hom.: 11730

Bravo AF: 0.252

Asia WGS AF: 0.207 AC: 718 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.4
DANN	Benign	0.36

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs11718446; hg19: chr3-101552553;