ENST00000606253.5:c.962G>T

Variant names:

• chr19-35896080-C-A
• rs768512398
• ENST00000606253.5:c.962G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000606253.5(NFKBID):​c.962G>T​(p.Arg321Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R321H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NFKBID ENST00000606253.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.106

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0688996).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKBID	NM_032721.3	c.962G>T	p.Arg321Leu	missense_variant	Exon 9 of 12		NP_116110.2
NFKBID	NM_139239.5	c.932G>T	p.Arg311Leu	missense_variant	Exon 9 of 12		NP_640332.2
NFKBID	NM_001365706.3	c.932G>T	p.Arg311Leu	missense_variant	Exon 9 of 10		NP_001352635.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFKBID	ENST00000641389.3	c.932G>T	p.Arg311Leu	missense_variant	Exon 9 of 12			ENSP00000493265.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Immunodeficiency, common variable, 12 Uncertain:1

May 21, 2020

UOSD Laboratory of Genetics & Genomics of Rare Diseases, Istituto Giannina Gaslini

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.061	.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.61	T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.069	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	.;L;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.1	.;N;.
REVEL	Benign	0.083
Sift	Benign	0.28	.;T;.
Sift4G	Benign	0.31	.;T;.
Polyphen		0.0	.;B;B
Vest4		0.072
MutPred		0.58		.;Loss of phosphorylation at S171 (P = 0.1497);.;
MVP		0.12
MPC		0.91
ClinPred		0.058	T
GERP RS		-2.2
Varity_R		0.048

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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

Other links and lift over

dbSNP: rs768512398; hg19: chr19-36386982;