rs1957106

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr14-35404564-G-A
• chr14-35404564-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_020529.3(NFKBIA):​c.81C>T​(p.Asp27Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 1,591,188 control chromosomes in the GnomAD database, including 68,258 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5326 hom., cov: 32)
  • Exomes 𝑓: 0.29 (62932 hom.)
• Consequence: NFKBIA NM_020529.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• 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: 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 14-35404564-G-A is Benign according to our data. Variant chr14-35404564-G-A is described in ClinVar as Benign. ClinVar VariationId is 313117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.027 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.324 is higher than 0.05.

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.81C>T	p.Asp27Asp	synonymous	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.81C>T	p.Asp27Asp	synonymous	Exon 1 of 6	ENSP00000216797.6	P25963
	NFKBIA	ENST00000860149.1		c.81C>T	p.Asp27Asp	synonymous	Exon 1 of 6	ENSP00000530208.1
	NFKBIA	ENST00000697961.1		c.81C>T	p.Asp27Asp	synonymous	Exon 1 of 5	ENSP00000513487.1	A0A8V8TLC3

Frequencies

GnomAD3 genomes AF: 0.251 AC: 38116 AN: 151672 Hom.: 5315 Cov.: 32

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.225

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.260

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.387

Gnomad MID AF: 0.213

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.236

GnomAD2 exomes AF: 0.284 AC: 61676 AN: 217444 AF XY: 0.292

Gnomad AFR exome AF: 0.140

Gnomad AMR exome AF: 0.181

Gnomad ASJ exome AF: 0.218

Gnomad EAS exome AF: 0.265

Gnomad FIN exome AF: 0.411

Gnomad NFE exome AF: 0.306

Gnomad OTH exome AF: 0.277

GnomAD4 exome AF: 0.292 AC: 419627 AN: 1439408 Hom.: 62932 Cov.: 39 AF XY: 0.293 AC XY: 209963 AN XY: 715466

African (AFR) AF: 0.136 AC: 4357 AN: 31998

American (AMR) AF: 0.182 AC: 7720 AN: 42330

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 5438 AN: 25730

East Asian (EAS) AF: 0.263 AC: 9913 AN: 37738

South Asian (SAS) AF: 0.319 AC: 26607 AN: 83318

European-Finnish (FIN) AF: 0.407 AC: 20639 AN: 50726

Middle Eastern (MID) AF: 0.218 AC: 1248 AN: 5734

European-Non Finnish (NFE) AF: 0.297 AC: 327276 AN: 1102406

Other (OTH) AF: 0.276 AC: 16429 AN: 59428

GnomAD4 genome AF: 0.251 AC: 38147 AN: 151780 Hom.: 5326 Cov.: 32 AF XY: 0.255 AC XY: 18942 AN XY: 74204

African (AFR) AF: 0.145 AC: 5994 AN: 41470

American (AMR) AF: 0.192 AC: 2926 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 715 AN: 3470

East Asian (EAS) AF: 0.260 AC: 1336 AN: 5146

South Asian (SAS) AF: 0.338 AC: 1629 AN: 4826

European-Finnish (FIN) AF: 0.387 AC: 4054 AN: 10464

Middle Eastern (MID) AF: 0.205 AC: 60 AN: 292

European-Non Finnish (NFE) AF: 0.305 AC: 20716 AN: 67834

Other (OTH) AF: 0.244 AC: 513 AN: 2104

Alfa AF: 0.274 Hom.: 10182

Bravo AF: 0.229

Asia WGS AF: 0.295 AC: 1001 AN: 3406

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Ectodermal dysplasia and immunodeficiency 2 (3)
-	-	2	not specified (2)
-	-	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	9.4
DANN	Benign	0.95
PhyloP100		0.027
PromoterAI		0.0049	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Mutation Taster		=97/3	polymorphism (auto)

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; COSMIC: COSV53751429; COSMIC: COSV53751429;