6-44261730-C-T

Position:

• chr6-44261730-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004556.3(NFKBIE):​c.587G>A​(p.Cys196Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NFKBIE NM_004556.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

Genes affected

NFKBIE (HGNC:7799): (NFKB inhibitor epsilon) The protein encoded by this gene binds to components of NF-kappa-B, trapping the complex in the cytoplasm and preventing it from activating genes in the nucleus. Phosphorylation of the encoded protein targets it for destruction by the ubiquitin pathway, which activates NF-kappa-B by making it available to translocate to the nucleus. [provided by RefSeq, Sep 2011]

POLR1C (HGNC:20194): (RNA polymerase I and III subunit C) The protein encoded by this gene is a subunit of both RNA polymerase I and RNA polymerase III complexes. The encoded protein is part of the Pol core element. Mutations in this gene have been associated with Treacher Collins syndrome (TCS) and hypomyelinating leukodystrophy 11. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFKBIE	NM_004556.3	c.587G>A	p.Cys196Tyr	missense_variant	3/6	ENST00000619360.6	NP_004547.3
POLR1C	NM_001318876.2	c.946-180160C>T		intron_variant			NP_001305805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFKBIE	ENST00000619360.6	c.587G>A	p.Cys196Tyr	missense_variant	3/6	1	NM_004556.3	ENSP00000480216.1
NFKBIE	ENST00000275015.9	c.1004G>A	p.Cys335Tyr	missense_variant	3/6	1		ENSP00000275015.3
NFKBIE	ENST00000477930.2	n.*58G>A		non_coding_transcript_exon_variant	2/3	3		ENSP00000454778.2
NFKBIE	ENST00000477930.2	n.*58G>A		3_prime_UTR_variant	2/3	3		ENSP00000454778.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2021

The c.1004G>A (p.C335Y) alteration is located in exon 3 (coding exon 3) of the NFKBIE gene. This alteration results from a G to A substitution at nucleotide position 1004, causing the cysteine (C) at amino acid position 335 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.065	T;T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.9	.;M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-9.1	.;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	.;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	.;D
Vest4		0.90
MutPred		0.71		.;Loss of disorder (P = 0.0447);
MVP		0.77
MPC		2.4
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.91
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-44229467;