14-36516817-CA-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_001079668.3(NKX2-1):c.*460del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.12 (1408 hom., cov: 0)
  • Exomes 𝑓: 0.19 (32 hom.)
• Consequence: NKX2-1 NM_001079668.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -1.44

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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.265 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NKX2-1	NM_001079668.3	c.*460del		3_prime_UTR_variant	3/3	ENST00000354822.7
SFTA3	NR_161364.1	n.89+2650del		intron_variant, non_coding_transcript_variant
NKX2-1	NM_003317.4	c.*460del		3_prime_UTR_variant	2/2
SFTA3	NR_161365.1	n.89+2650del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NKX2-1	ENST00000354822.7	c.*460del		3_prime_UTR_variant	3/3	1	NM_001079668.3	P4
NKX2-1	ENST00000498187.6	c.*460del		3_prime_UTR_variant	2/2	1		A1
	ENST00000634305.1	n.322+67995del		intron_variant, non_coding_transcript_variant		5
NKX2-1	ENST00000518149.5	c.*460del		3_prime_UTR_variant	3/3	5		A1

Frequencies

GnomAD3 genomes AF: 0.123 AC: 17430 AN: 142196 Hom.: 1398 Cov.: 0

Gnomad AFR AF: 0.0485

Gnomad AMI AF: 0.0930

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.0969

Gnomad EAS AF: 0.277

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.160

Gnomad MID AF: 0.0445

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.112

GnomAD4 exome AF: 0.194 AC: 13891 AN: 71702 Hom.: 32 Cov.: 0 AF XY: 0.191 AC XY: 6304 AN XY: 32964

Gnomad4 AFR exome AF: 0.173

Gnomad4 AMR exome AF: 0.275

Gnomad4 ASJ exome AF: 0.165

Gnomad4 EAS exome AF: 0.287

Gnomad4 SAS exome AF: 0.245

Gnomad4 FIN exome AF: 0.179

Gnomad4 NFE exome AF: 0.174

Gnomad4 OTH exome AF: 0.179

GnomAD4 genome AF: 0.123 AC: 17470 AN: 142256 Hom.: 1408 Cov.: 0 AF XY: 0.129 AC XY: 8883 AN XY: 68814

Gnomad4 AFR AF: 0.0489

Gnomad4 AMR AF: 0.254

Gnomad4 ASJ AF: 0.0969

Gnomad4 EAS AF: 0.278

Gnomad4 SAS AF: 0.183

Gnomad4 FIN AF: 0.160

Gnomad4 NFE AF: 0.118

Gnomad4 OTH AF: 0.113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Brain-lung-thyroid syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Benign hereditary chorea Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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: rs5807883; hg19: chr14-36986022;