14-36517098-GAAAA-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001079668.3(NKX2-1):c.*176_*179del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 1,159,822 control chromosomes in the GnomAD database, including 36,317 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.19 (3600 hom., cov: 28)
  • Exomes 𝑓: 0.24 (32717 hom.)
• Consequence: NKX2-1 NM_001079668.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.25

Genes affected

NKX2-1 (HGNC:11825): (NK2 homeobox 1) This gene encodes a protein initially identified as a thyroid-specific transcription factor. The encoded protein binds to the thyroglobulin promoter and regulates the expression of thyroid-specific genes but has also been shown to regulate the expression of genes involved in morphogenesis. Mutations and deletions in this gene are associated with benign hereditary chorea, choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress, and may be associated with thyroid cancer. Multiple transcript variants encoding different isoforms have been found for this gene. This gene shares the symbol/alias 'TTF1' with another gene, transcription termination factor 1, which plays a role in ribosomal gene transcription. [provided by RefSeq, Feb 2014]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 14-36517098-GAAAA-G is Benign according to our data. Variant chr14-36517098-GAAAA-G is described in ClinVar as [Benign]. Clinvar id is 1291743.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NKX2-1	NM_001079668.3	c.*176_*179del		3_prime_UTR_variant	3/3	ENST00000354822.7
SFTA3	NR_161364.1	n.89+2366_89+2369del		intron_variant, non_coding_transcript_variant
NKX2-1	NM_003317.4	c.*176_*179del		3_prime_UTR_variant	2/2
SFTA3	NR_161365.1	n.89+2366_89+2369del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NKX2-1	ENST00000354822.7	c.*176_*179del		3_prime_UTR_variant	3/3	1	NM_001079668.3	P4
NKX2-1	ENST00000498187.6	c.*176_*179del		3_prime_UTR_variant	2/2	1		A1
	ENST00000634305.1	n.322+68265_322+68268del		intron_variant, non_coding_transcript_variant		5
NKX2-1	ENST00000518149.5	c.*176_*179del		3_prime_UTR_variant	3/3	5		A1

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29331 AN: 150682 Hom.: 3602 Cov.: 28

Gnomad AFR AF: 0.0505

Gnomad AMI AF: 0.356

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.0868

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.224

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.227

GnomAD4 exome AF: 0.236 AC: 238375 AN: 1009024 Hom.: 32717 AF XY: 0.236 AC XY: 115951 AN XY: 491768

Gnomad4 AFR exome AF: 0.0381

Gnomad4 AMR exome AF: 0.219

Gnomad4 ASJ exome AF: 0.290

Gnomad4 EAS exome AF: 0.105

Gnomad4 SAS exome AF: 0.132

Gnomad4 FIN exome AF: 0.207

Gnomad4 NFE exome AF: 0.253

Gnomad4 OTH exome AF: 0.227

GnomAD4 genome AF: 0.194 AC: 29325 AN: 150798 Hom.: 3600 Cov.: 28 AF XY: 0.194 AC XY: 14253 AN XY: 73480

Gnomad4 AFR AF: 0.0504

Gnomad4 AMR AF: 0.238

Gnomad4 ASJ AF: 0.304

Gnomad4 EAS AF: 0.0870

Gnomad4 SAS AF: 0.142

Gnomad4 FIN AF: 0.222

Gnomad4 NFE AF: 0.272

Gnomad4 OTH AF: 0.225

Asia WGS AF: 0.138 AC: 479 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 16, 2019

- -

Computational scores

Source: dbNSFP v4.3

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: rs200848675; hg19: chr14-36986303;