19-35890005-G-A

Variant names:

• chr19-35890005-G-A
• rs748957539
• ENST00000606253.5:c.1229C>T

Variant summary

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

The NM_032721.3(NFKBID):​c.1229C>T​(p.Pro410Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,456,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: NFKBID NM_032721.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 3.15

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=0.14906737).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKBID	NM_032721.3	c.1229C>T	p.Pro410Leu	missense_variant	Exon 11 of 12		NP_116110.2
NFKBID	NM_139239.5	c.1199C>T	p.Pro400Leu	missense_variant	Exon 11 of 12		NP_640332.2
NFKBID	NM_001321831.2	c.818C>T	p.Pro273Leu	missense_variant	Exon 11 of 12		NP_001308760.1
NFKBID	NM_001365705.1	c.773C>T	p.Pro258Leu	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	c.1199C>T	p.Pro400Leu	missense_variant	Exon 11 of 12			ENSP00000493265.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000254 AC: 6 AN: 236264 Hom.: 0 AF XY: 0.0000308 AC XY: 4 AN XY: 129752

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000205

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000281

Gnomad OTH exome AF: 0.000173

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1456284 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 724524

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000602

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ExAC AF: 0.0000166 AC: 2

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	0.083
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.021	.;T;.
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.053
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.85	.;L;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.080	.;N;.
REVEL	Benign	0.15
Sift	Benign	0.36	.;T;.
Sift4G	Benign	0.29	.;T;.
Polyphen		0.95, 0.99	.;P;D
Vest4		0.25
MutPred		0.35		.;Loss of glycosylation at P258 (P = 0.0194);.;
MVP		0.68
MPC		1.3
ClinPred		0.18	T
GERP RS		3.8
Varity_R		0.059

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

Other links and lift over

dbSNP: rs748957539; hg19: chr19-36380907; COSMIC: COSV100573233; COSMIC: COSV100573233;