14-36517067-T-TA

Position:

• chr14-36517067-T-TA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001079668.3(NKX2-1):​c.*210dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00778 in 873,584 control chromosomes in the GnomAD database, including 19 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0065 (6 hom., cov: 29)
  • Exomes 𝑓: 0.0080 (13 hom.)
• Consequence: NKX2-1 NM_001079668.3 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.620

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]

SFTA3 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 14-36517067-T-TA is Benign according to our data. Variant chr14-36517067-T-TA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 313132.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00648 (938/144750) while in subpopulation NFE AF= 0.0104 (677/65206). AF 95% confidence interval is 0.00973. There are 6 homozygotes in gnomad4. There are 429 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 938 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NKX2-1	NM_001079668.3	c.*210dupT		3_prime_UTR_variant	3/3	ENST00000354822.7	NP_001073136.1
NKX2-1	NM_003317.4	c.*210dupT		3_prime_UTR_variant	2/2		NP_003308.1
SFTA3	NR_161364.1	n.89+2400dupT		intron_variant
SFTA3	NR_161365.1	n.89+2400dupT		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NKX2-1	ENST00000354822	c.*210dupT		3_prime_UTR_variant	3/3	1	NM_001079668.3	ENSP00000346879.6
SFTA3	ENST00000546983.2	n.373+1917dupT		intron_variant		4		ENSP00000449302.2

Frequencies

GnomAD3 genomes AF: 0.00649 AC: 939 AN: 144634 Hom.: 6 Cov.: 29

Gnomad AFR AF: 0.00243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00708

Gnomad ASJ AF: 0.000301

Gnomad EAS AF: 0.00595

Gnomad SAS AF: 0.00131

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00342

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.00462

GnomAD4 exome AF: 0.00804 AC: 5860 AN: 728834 Hom.: 13 Cov.: 10 AF XY: 0.00780 AC XY: 2827 AN XY: 362248

Gnomad4 AFR exome AF: 0.0117

Gnomad4 AMR exome AF: 0.00819

Gnomad4 ASJ exome AF: 0.00280

Gnomad4 EAS exome AF: 0.0126

Gnomad4 SAS exome AF: 0.00112

Gnomad4 FIN exome AF: 0.00252

Gnomad4 NFE exome AF: 0.00861

Gnomad4 OTH exome AF: 0.00869

GnomAD4 genome AF: 0.00648 AC: 938 AN: 144750 Hom.: 6 Cov.: 29 AF XY: 0.00610 AC XY: 429 AN XY: 70300

Gnomad4 AFR AF: 0.00240

Gnomad4 AMR AF: 0.00707

Gnomad4 ASJ AF: 0.000301

Gnomad4 EAS AF: 0.00596

Gnomad4 SAS AF: 0.00132

Gnomad4 FIN AF: 0.00189

Gnomad4 NFE AF: 0.0104

Gnomad4 OTH AF: 0.00457

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2023

NKX2-1: BS1, BS2 -

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: rs886050480; hg19: chr14-36986272;