Genetic Variant NFKBID:p.Arg417Trp (chr19-35889985-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_032721.3(NFKBID):c.1249C>T(p.Arg417Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000823 in 1,458,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

NFKBID
NM_032721.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.44

Variant links:

Genes affected

NFKBID (HGNC:15671): (NFKB inhibitor delta) Predicted to enable NF-kappaB binding activity. Predicted to be involved in T cell receptor signaling pathway; positive regulation of T-helper 17 cell differentiation; and regulation of gene expression. Predicted to act upstream of or within several processes, including negative regulation of NF-kappaB transcription factor activity; negative regulation of T cell differentiation in thymus; and positive regulation of thymocyte apoptotic process. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

NFKBID links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.797

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
NFKBID	NM_032721.3 link	c.1249C>T	p.Arg417Trp	missense_variant	Exon 11 of 12	NP_116110.2
NFKBID	NM_139239.5 link	c.1219C>T	p.Arg407Trp	missense_variant	Exon 11 of 12	NP_640332.2	Q8NI38-1
NFKBID	NM_001321831.2 link	c.838C>T	p.Arg280Trp	missense_variant	Exon 11 of 12	NP_001308760.1
NFKBID	NM_001365705.1 link	c.793C>T	p.Arg265Trp	missense_variant	Exon 11 of 12	NP_001352634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFKBID	ENST00000641389.3 link	c.1219C>T	p.Arg407Trp	missense_variant	Exon 11 of 12			ENSP00000493265.2		A0A286YF31

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000825

AC:

AN:

242296

Hom.:

AF XY:

0.00000755

AC XY:

AN XY:

132388

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000563

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000910

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000823

AC:

AN:

1458612

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

725676

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000900

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000830

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.793C>T (p.R265W) alteration is located in exon 11 (coding exon 8) of the NFKBID gene. This alteration results from a C to T substitution at nucleotide position 793, causing the arginine (R) at amino acid position 265 to be replaced by a tryptophan (W). 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

Benign

0.14

BayesDel_addAF

Uncertain

0.044

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.28

.;T;.

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.80

D;D;D

MetaSVM

Uncertain

0.046

MutationAssessor

Uncertain

2.5

.;M;.

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-6.2

.;D;.

REVEL

Uncertain

0.45

Sift

Pathogenic

0.0

.;D;.

Sift4G

Uncertain

0.0020

.;D;.

Polyphen

1.0

.;D;D

Vest4

0.45

MutPred

0.60

.;Loss of disorder (P = 0.004);.;

MVP

0.52

MPC

1.8

ClinPred

0.99

GERP RS

3.8

Varity_R

0.59

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over