19-35896779-C-A

Variant names:

• chr19-35896779-C-A
• rs1314908795
• ENST00000606253.5:c.661G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032721.3(NFKBID):​c.661G>T​(p.Ala221Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: NFKBID NM_032721.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.90

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41667193).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKBID	NM_032721.3	c.661G>T	p.Ala221Ser	missense_variant	Exon 6 of 12		NP_116110.2
NFKBID	NM_139239.5	c.631G>T	p.Ala211Ser	missense_variant	Exon 6 of 12		NP_640332.2
NFKBID	NM_001365706.3	c.631G>T	p.Ala211Ser	missense_variant	Exon 6 of 10		NP_001352635.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFKBID	ENST00000641389.3	c.631G>T	p.Ala211Ser	missense_variant	Exon 6 of 12			ENSP00000493265.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.205G>T (p.A69S) alteration is located in exon 6 (coding exon 3) of the NFKBID gene. This alteration results from a G to T substitution at nucleotide position 205, causing the alanine (A) at amino acid position 69 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	.;T;.;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.86	D;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.42	T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.5	.;L;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.9	.;N;.;.
REVEL	Benign	0.26
Sift	Benign	0.060	.;T;.;.
Sift4G	Uncertain	0.041	.;D;.;.
Polyphen		1.0	.;D;D;.
Vest4		0.57
MutPred		0.56		.;Gain of relative solvent accessibility (P = 0.0479);.;.;
MVP		0.39
MPC		1.7
ClinPred		0.93	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24

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: rs1314908795; hg19: chr19-36387681;