14-35404550-C-T

Variant names:

• chr14-35404550-C-T
• rs28933100
• NM_020529.3:c.95G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM1 PM2 PM5 PP5_Very_Strong

The NM_020529.3(NFKBIA):​c.95G>A​(p.Ser32Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002122672: Experimental studies have shown that this missense change affects NFKBIA function (PMID:29948576).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S32R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NFKBIA NM_020529.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.54
• Publications: 26 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: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• ectodermal dysplasia and immune deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000310246 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002122672: Experimental studies have shown that this missense change affects NFKBIA function (PMID: 29948576).
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_020529.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-35404549-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 590310.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP5: Variant 14-35404550-C-T is Pathogenic according to our data. Variant chr14-35404550-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 590311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020529.3. 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
	NFKBIA	NM_020529.3	MANE Select	c.95G>A	p.Ser32Asn	missense	Exon 1 of 6	NP_065390.1	P25963

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKBIA	ENST00000216797.10	TSL:1 MANE Select	c.95G>A	p.Ser32Asn	missense	Exon 1 of 6	ENSP00000216797.6	P25963
	NFKBIA	ENST00000860149.1		c.95G>A	p.Ser32Asn	missense	Exon 1 of 6	ENSP00000530208.1
	NFKBIA	ENST00000697961.1		c.95G>A	p.Ser32Asn	missense	Exon 1 of 5	ENSP00000513487.1	A0A8V8TLC3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Ectodermal dysplasia and immunodeficiency 2 (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
PhyloP100		5.5
PromoterAI		0.0012	Neutral
Varity_R		0.65
gMVP		0.33
Mutation Taster		=7/93	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs28933100; hg19: chr14-35873756; COSMIC: COSV53752100;