14-35404564-G-T

Variant names:

• chr14-35404564-G-T
• rs1957106
• NM_020529.3:c.81C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_020529.3(NFKBIA):​c.81C>A​(p.Asp27Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D27D) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NFKBIA NM_020529.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0270
• Publications: 37 publications found

Genes affected

NFKBIA (HGNC:7797): (NFKB inhibitor alpha) This gene encodes a member of the NF-kappa-B inhibitor family, which contain multiple ankrin repeat domains. The encoded protein interacts with REL dimers to inhibit NF-kappa-B/REL complexes which are involved in inflammatory responses. The encoded protein moves between the cytoplasm and the nucleus via a nuclear localization signal and CRM1-mediated nuclear export. Mutations in this gene have been found in ectodermal dysplasia anhidrotic with T-cell immunodeficiency autosomal dominant disease. [provided by RefSeq, Aug 2011]

NFKBIA Gene-Disease associations (from GenCC):

• ectodermal dysplasia and immunodeficiency 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• ectodermal dysplasia and immune deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000310246 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_020529.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15325072).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFKBIA	NM_020529.3	c.81C>A	p.Asp27Glu	missense_variant	Exon 1 of 6	ENST00000216797.10	NP_065390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFKBIA	ENST00000216797.10	c.81C>A	p.Asp27Glu	missense_variant	Exon 1 of 6	1	NM_020529.3	ENSP00000216797.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	12
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;T;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.57
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.62	T;T;T
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.97	L;.;.
PhyloP100		0.027
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	0.12	N;N;N
REVEL	Benign	0.24
Sift	Benign	0.78	T;T;D
Sift4G	Benign	1.0	T;T;.
Vest4		0.21
ClinPred		0.095	T
GERP RS		1.9
PromoterAI		-0.015	Neutral
Varity_R		0.14
gMVP		0.11
Mutation Taster		=89/11	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: rs1957106; hg19: chr14-35873770;