14-36519723-A-AAG

Position:

• chr14-36519723-A-AAG

Variant summary

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

The NM_001079668.3(NKX2-1):​c.77+329_77+330insCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,443,664 control chromosomes in the GnomAD database, including 2,347 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.084 (650 hom., cov: 31)
  • Exomes 𝑓: 0.10 (1697 hom.)
• Consequence: NKX2-1 NM_001079668.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.683

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]

NKX2-1-AS1 (HGNC:40585): (NKX2-1 antisense RNA 1)

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 14-36519723-A-AAG is Benign according to our data. Variant chr14-36519723-A-AAG is described in ClinVar as [Benign]. Clinvar id is 1296646.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NKX2-1	NM_001079668.3	c.77+329_77+330insCT		intron_variant		ENST00000354822.7	NP_001073136.1
NKX2-1-AS1	NR_103710.1	n.402+59_402+60dup		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NKX2-1	ENST00000354822.7	c.77+329_77+330insCT		intron_variant		1	NM_001079668.3	ENSP00000346879	P4
NKX2-1-AS1	ENST00000521292.2	n.402+59_402+60dup		intron_variant, non_coding_transcript_variant		2
	ENST00000634305.1	n.322+70901_322+70902dup		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0839 AC: 12668 AN: 151054 Hom.: 650 Cov.: 31

Gnomad AFR AF: 0.0244

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.0891

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.000970

Gnomad SAS AF: 0.0857

Gnomad FIN AF: 0.0984

Gnomad MID AF: 0.202

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.102

GnomAD4 exome AF: 0.103 AC: 133458 AN: 1292502 Hom.: 1697 Cov.: 28 AF XY: 0.103 AC XY: 65451 AN XY: 633982

Gnomad4 AFR exome AF: 0.0220

Gnomad4 AMR exome AF: 0.0608

Gnomad4 ASJ exome AF: 0.135

Gnomad4 EAS exome AF: 0.000571

Gnomad4 SAS exome AF: 0.0917

Gnomad4 FIN exome AF: 0.0924

Gnomad4 NFE exome AF: 0.110

Gnomad4 OTH exome AF: 0.102

GnomAD4 genome AF: 0.0838 AC: 12668 AN: 151162 Hom.: 650 Cov.: 31 AF XY: 0.0831 AC XY: 6135 AN XY: 73842

Gnomad4 AFR AF: 0.0244

Gnomad4 AMR AF: 0.0892

Gnomad4 ASJ AF: 0.160

Gnomad4 EAS AF: 0.000973

Gnomad4 SAS AF: 0.0862

Gnomad4 FIN AF: 0.0984

Gnomad4 NFE AF: 0.118

Gnomad4 OTH AF: 0.100

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 20, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs149047715; hg19: chr14-36988928;