19-35890005-G-T

Variant names:

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

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>A​(p.Pro400Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,206 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P400L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NFKBID NM_139239.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.15
• Publications: 0 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=0.17338356).

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>A	p.Pro400Gln	missense	Exon 11 of 12	NP_640332.2	A0A286YF31
	NFKBID	NM_032721.3		c.1229C>A	p.Pro410Gln	missense	Exon 11 of 12	NP_116110.2
	NFKBID	NM_001321831.2		c.818C>A	p.Pro273Gln	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>A	p.Pro400Gln	missense	Exon 11 of 12	ENSP00000493265.2	A0A286YF31
	NFKBID	ENST00000606253.5	TSL:1	c.1229C>A	p.Pro410Gln	missense	Exon 11 of 12	ENSP00000475712.2	Q8NI38-2
	NFKBID	ENST00000590828.5	TSL:1	n.*280C>A		non_coding_transcript_exon	Exon 5 of 6	ENSP00000467127.1	K7ENW9

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1456286 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 724526

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44532

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26040

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49872

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110704

Other (OTH) AF: 0.00 AC: 0 AN: 60126

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74418

African (AFR) AF: 0.00 AC: 0 AN: 41542

American (AMR) AF: 0.0000654 AC: 1 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67986

Other (OTH) AF: 0.00 AC: 0 AN: 2114

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.021
Eigen_PC	Benign	0.0011
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.050	N
PhyloP100		3.1
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.17
Sift	Benign	0.57	T
Sift4G	Benign	0.54	T
Polyphen		0.98	D
Vest4		0.27
MutPred		0.29		Loss of glycosylation at P258 (P = 0.0194)
MVP		0.64
MPC		1.6
ClinPred		0.50	D
GERP RS		3.8
Varity_R		0.059
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;