14-35402201-A-G

Variant names:

• chr14-35402201-A-G
• rs1022714
• NM_020529.3:c.907-141T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020529.3(NFKBIA):​c.907-141T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.792 in 1,192,596 control chromosomes in the GnomAD database, including 375,242 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (49107 hom., cov: 29)
  • Exomes 𝑓: 0.79 (326135 hom.)
• Consequence: NFKBIA NM_020529.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0530
• Publications: 13 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 14-35402201-A-G is Benign according to our data. Variant chr14-35402201-A-G is described in ClinVar as Benign. ClinVar VariationId is 1279397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.835 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKBIA	NM_020529.3	MANE Select	c.907-141T>C		intron	N/A	NP_065390.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKBIA	ENST00000216797.10	TSL:1 MANE Select	c.907-141T>C		intron	N/A	ENSP00000216797.6
	NFKBIA	ENST00000557459.2	TSL:2	n.1594T>C		non_coding_transcript_exon	Exon 3 of 3
	NFKBIA	ENST00000697958.1		n.1816T>C		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.805 AC: 121803 AN: 151396 Hom.: 49052 Cov.: 29

Gnomad AFR AF: 0.818

Gnomad AMI AF: 0.653

Gnomad AMR AF: 0.837

Gnomad ASJ AF: 0.743

Gnomad EAS AF: 0.723

Gnomad SAS AF: 0.857

Gnomad FIN AF: 0.807

Gnomad MID AF: 0.763

Gnomad NFE AF: 0.797

Gnomad OTH AF: 0.783

GnomAD4 exome AF: 0.790 AC: 822398 AN: 1041082 Hom.: 326135 AF XY: 0.792 AC XY: 423481 AN XY: 534474

African (AFR) AF: 0.810 AC: 19750 AN: 24384

American (AMR) AF: 0.880 AC: 35552 AN: 40392

Ashkenazi Jewish (ASJ) AF: 0.762 AC: 17662 AN: 23170

East Asian (EAS) AF: 0.682 AC: 25345 AN: 37178

South Asian (SAS) AF: 0.851 AC: 64726 AN: 76018

European-Finnish (FIN) AF: 0.801 AC: 41851 AN: 52248

Middle Eastern (MID) AF: 0.769 AC: 3666 AN: 4766

European-Non Finnish (NFE) AF: 0.784 AC: 577202 AN: 736518

Other (OTH) AF: 0.790 AC: 36644 AN: 46408

GnomAD4 genome AF: 0.805 AC: 121919 AN: 151514 Hom.: 49107 Cov.: 29 AF XY: 0.804 AC XY: 59463 AN XY: 73940

African (AFR) AF: 0.818 AC: 33712 AN: 41216

American (AMR) AF: 0.837 AC: 12763 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.743 AC: 2580 AN: 3472

East Asian (EAS) AF: 0.723 AC: 3719 AN: 5144

South Asian (SAS) AF: 0.857 AC: 4120 AN: 4810

European-Finnish (FIN) AF: 0.807 AC: 8371 AN: 10374

Middle Eastern (MID) AF: 0.755 AC: 222 AN: 294

European-Non Finnish (NFE) AF: 0.797 AC: 54185 AN: 67952

Other (OTH) AF: 0.787 AC: 1655 AN: 2102

Alfa AF: 0.800 Hom.: 61690

Bravo AF: 0.806

Asia WGS AF: 0.816 AC: 2840 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.4
DANN	Benign	0.75
PhyloP100		-0.053
Mutation Taster		=100/0	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: rs1022714; hg19: chr14-35871407;