14-36516985-A-AC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001079668.3(NKX2-1):c.*292_*293insG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 459,282 control chromosomes in the GnomAD database, including 11,758 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3711 hom., cov: 26)
  • Exomes 𝑓: 0.21 (8047 hom.)
• Consequence: NKX2-1 NM_001079668.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.22

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 -16 ACMG points.

• BP6: Variant 14-36516985-A-AC is Benign according to our data. Variant chr14-36516985-A-AC is described in ClinVar as [Benign]. Clinvar id is 313131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.271 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NKX2-1	NM_001079668.3	c.*292_*293insG		3_prime_UTR_variant	3/3	ENST00000354822.7
SFTA3	NR_161364.1	n.89+2482_89+2483insG		intron_variant, non_coding_transcript_variant
NKX2-1	NM_003317.4	c.*292_*293insG		3_prime_UTR_variant	2/2
SFTA3	NR_161365.1	n.89+2482_89+2483insG		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NKX2-1	ENST00000354822.7	c.*292_*293insG		3_prime_UTR_variant	3/3	1	NM_001079668.3	P4
NKX2-1	ENST00000498187.6	c.*292_*293insG		3_prime_UTR_variant	2/2	1		A1
	ENST00000634305.1	n.322+68152dup		intron_variant, non_coding_transcript_variant		5
NKX2-1	ENST00000518149.5	c.*292_*293insG		3_prime_UTR_variant	3/3	5		A1

Frequencies

GnomAD3 genomes AF: 0.199 AC: 29932 AN: 150532 Hom.: 3712 Cov.: 26

Gnomad AFR AF: 0.0521

Gnomad AMI AF: 0.362

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.0891

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.240

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.274

Gnomad OTH AF: 0.231

GnomAD4 exome AF: 0.213 AC: 65669 AN: 308644 Hom.: 8047 Cov.: 5 AF XY: 0.209 AC XY: 33109 AN XY: 158444

Gnomad4 AFR exome AF: 0.0417

Gnomad4 AMR exome AF: 0.214

Gnomad4 ASJ exome AF: 0.287

Gnomad4 EAS exome AF: 0.0976

Gnomad4 SAS exome AF: 0.137

Gnomad4 FIN exome AF: 0.173

Gnomad4 NFE exome AF: 0.243

Gnomad4 OTH exome AF: 0.220

GnomAD4 genome AF: 0.199 AC: 29928 AN: 150638 Hom.: 3711 Cov.: 26 AF XY: 0.199 AC XY: 14654 AN XY: 73486

Gnomad4 AFR AF: 0.0520

Gnomad4 AMR AF: 0.242

Gnomad4 ASJ AF: 0.307

Gnomad4 EAS AF: 0.0893

Gnomad4 SAS AF: 0.145

Gnomad4 FIN AF: 0.240

Gnomad4 NFE AF: 0.274

Gnomad4 OTH AF: 0.229

Alfa AF: 0.220 Hom.: 370

Asia WGS AF: 0.144 AC: 502 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brain-lung-thyroid syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 14, 2018

- -

Benign hereditary chorea Benign:1

Benign, 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: rs140427692; hg19: chr14-36986190;