14-36517091-A-AGGGTGGG

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS1

The NM_001079668.3(NKX2-1):c.*186_*187insCCCACCC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0014 (4 hom.)
  • Failed GnomAD Quality Control
• Consequence: NKX2-1 NM_001079668.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0890

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 Likely_benign. Variant got -6 ACMG points.

• BP6: Variant 14-36517091-A-AGGGTGGG is Benign according to our data. Variant chr14-36517091-A-AGGGTGGG is described in ClinVar as [Likely_benign]. Clinvar id is 2570877.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00142 (1241/876360) while in subpopulation NFE AF= 0.0016 (1104/691648). AF 95% confidence interval is 0.00152. There are 4 homozygotes in gnomad4_exome. There are 632 alleles in male gnomad4_exome subpopulation. Median coverage is 12. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NKX2-1	NM_001079668.3	c.*186_*187insCCCACCC		3_prime_UTR_variant	3/3	ENST00000354822.7
SFTA3	NR_161364.1	n.89+2376_89+2377insCCCACCC		intron_variant, non_coding_transcript_variant
NKX2-1	NM_003317.4	c.*186_*187insCCCACCC		3_prime_UTR_variant	2/2
SFTA3	NR_161365.1	n.89+2376_89+2377insCCCACCC		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NKX2-1	ENST00000354822.7	c.*186_*187insCCCACCC		3_prime_UTR_variant	3/3	1	NM_001079668.3	P4
NKX2-1	ENST00000498187.6	c.*186_*187insCCCACCC		3_prime_UTR_variant	2/2	1		A1
	ENST00000634305.1	n.322+68257_322+68258insTGGGGGG		intron_variant, non_coding_transcript_variant		5
NKX2-1	ENST00000518149.5	c.*186_*187insCCCACCC		3_prime_UTR_variant	3/3	5		A1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 215 AN: 149882 Hom.: 0 Cov.: 28 FAILED QC

Gnomad AFR AF: 0.000318

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00159

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000389

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000823

Gnomad MID AF: 0.00645

Gnomad NFE AF: 0.00235

Gnomad OTH AF: 0.000972

GnomAD4 exome AF: 0.00142 AC: 1241 AN: 876360 Hom.: 4 Cov.: 12 AF XY: 0.00147 AC XY: 632 AN XY: 430598

Gnomad4 AFR exome AF: 0.000452

Gnomad4 AMR exome AF: 0.000798

Gnomad4 ASJ exome AF: 0.00150

Gnomad4 EAS exome AF: 0.000650

Gnomad4 SAS exome AF: 0.000413

Gnomad4 FIN exome AF: 0.000757

Gnomad4 NFE exome AF: 0.00160

Gnomad4 OTH exome AF: 0.000990

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00143 AC: 214 AN: 149964 Hom.: 0 Cov.: 28 AF XY: 0.00126 AC XY: 92 AN XY: 73042

Gnomad4 AFR AF: 0.000317

Gnomad4 AMR AF: 0.00153

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000390

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000823

Gnomad4 NFE AF: 0.00236

Gnomad4 OTH AF: 0.000962

Alfa AF: 0.000167 Hom.: 126

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2023

NKX2-1: BS1 -

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: rs141117763; hg19: chr14-36986296;