rs748957539

Variant names:

• chr19-35890005-G-A
• rs748957539
• NM_139239.5:c.1199C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-35890005-G-A
• chr19-35890005-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_139239.5(NFKBID):​c.1199C>T​(p.Pro400Leu) 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. 14/21 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. P400A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: NFKBID NM_139239.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 3.15
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14906737).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139239.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKBID	NM_139239.5	MANE Select	c.1199C>T	p.Pro400Leu	missense	Exon 11 of 12	NP_640332.2	A0A286YF31
	NFKBID	NM_032721.3		c.1229C>T	p.Pro410Leu	missense	Exon 11 of 12	NP_116110.2
	NFKBID	NM_001321831.2		c.818C>T	p.Pro273Leu	missense	Exon 11 of 12	NP_001308760.1	A0AAQ5BIF9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKBID	ENST00000641389.3	MANE Select	c.1199C>T	p.Pro400Leu	missense	Exon 11 of 12	ENSP00000493265.2	A0A286YF31
	NFKBID	ENST00000606253.5	TSL:1	c.1229C>T	p.Pro410Leu	missense	Exon 11 of 12	ENSP00000475712.2	Q8NI38-2
	NFKBID	ENST00000590828.5	TSL:1	n.*280C>T		non_coding_transcript_exon	Exon 5 of 6	ENSP00000467127.1	K7ENW9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000254 AC: 6 AN: 236264 AF XY: 0.0000308

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 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

African (AFR) AF: 0.0000299 AC: 1 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44530

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86164

European-Finnish (FIN) AF: 0.0000602 AC: 3 AN: 49872

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1110704

Other (OTH) AF: 0.0000333 AC: 2 AN: 60126

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000166 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Immunodeficiency, common variable, 12 (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.85	L
PhyloP100		3.1
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	P
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
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

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