19-35896791-C-A

Variant names:

• chr19-35896791-C-A
• rs112797384
• NM_139239.5:c.619G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_139239.5(NFKBID):​c.619G>T​(p.Ala207Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,614,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: NFKBID NM_139239.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.74
• Publications: 4 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22345623).

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.619G>T	p.Ala207Ser	missense	Exon 6 of 12	NP_640332.2	A0A286YF31
	NFKBID	NM_032721.3		c.649G>T	p.Ala217Ser	missense	Exon 6 of 12	NP_116110.2
	NFKBID	NM_001365706.3		c.619G>T	p.Ala207Ser	missense	Exon 6 of 10	NP_001352635.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKBID	ENST00000641389.3	MANE Select	c.619G>T	p.Ala207Ser	missense	Exon 6 of 12	ENSP00000493265.2	A0A286YF31
	NFKBID	ENST00000606253.5	TSL:1	c.649G>T	p.Ala217Ser	missense	Exon 6 of 12	ENSP00000475712.2	Q8NI38-2
	NFKBID	ENST00000585925.8	TSL:3	c.664G>T	p.Ala222Ser	missense	Exon 6 of 12	ENSP00000465684.4	K7EKM2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152180 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

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 AF: 0.0000198 AC: 29 AN: 1461710 Hom.: 0 Cov.: 33 AF XY: 0.0000206 AC XY: 15 AN XY: 727136

African (AFR) AF: 0.000388 AC: 13 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111878

Other (OTH) AF: 0.000248 AC: 15 AN: 60374

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152298 Hom.: 0 Cov.: 31 AF XY: 0.0000537 AC XY: 4 AN XY: 74474

African (AFR) AF: 0.0000722 AC: 3 AN: 41564

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.045	T
Eigen	Benign	-0.013
Eigen_PC	Benign	0.035
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		2.7
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.15
Sift	Benign	0.79	T
Sift4G	Benign	0.25	T
Polyphen		0.79	P
Vest4		0.43
MutPred		0.55		Loss of stability (P = 0.0959)
MVP		0.55
MPC		1.3
ClinPred		0.87	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
Mutation Taster		=91/9	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: rs112797384; hg19: chr19-36387693;