Genetic Variant NFKBID:p.His438Asn (chr19-35889922-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032721.3(NFKBID):c.1312C>A(p.His438Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,212 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

NFKBID
NM_032721.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.78

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
NFKBID	NM_032721.3 link	c.1312C>A	p.His438Asn	missense_variant	Exon 11 of 12	NP_116110.2
NFKBID	NM_139239.5 link	c.1282C>A	p.His428Asn	missense_variant	Exon 11 of 12	NP_640332.2	Q8NI38-1
NFKBID	NM_001321831.2 link	c.901C>A	p.His301Asn	missense_variant	Exon 11 of 12	NP_001308760.1
NFKBID	NM_001365705.1 link	c.856C>A	p.His286Asn	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.1282C>A	p.His428Asn	missense_variant	Exon 11 of 12			ENSP00000493265.2		A0A286YF31

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459212

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725680

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 03, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.856C>A (p.H286N) alteration is located in exon 11 (coding exon 8) of the NFKBID gene. This alteration results from a C to A substitution at nucleotide position 856, causing the histidine (H) at amino acid position 286 to be replaced by an asparagine (N). 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

Uncertain

0.53

BayesDel_addAF

Benign

-0.053

BayesDel_noAF

Benign

-0.31

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.50

.;D;.

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Benign

0.041

MetaRNN

Uncertain

0.48

T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Uncertain

2.2

.;M;.

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.5

.;D;.

REVEL

Benign

0.27

Sift

Uncertain

0.014

.;D;.

Sift4G

Uncertain

0.012

.;D;.

Polyphen

0.99, 1.0

.;D;D

Vest4

0.77

MutPred

0.42

.;Loss of catalytic residue at L288 (P = 0.2069);.;

MVP

0.52

MPC

1.9

ClinPred

0.98

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.51

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over