14-36517091-A-AGGGTG

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001079668.3(NKX2-1):c.*186_*187insCACCC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,025,388 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 28)
  • Exomes 𝑓: 0.0019 (6 hom.)
• 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 Benign. Variant got -10 ACMG points.

• BP6: Variant 14-36517091-A-AGGGTG is Benign according to our data. Variant chr14-36517091-A-AGGGTG is described in ClinVar as [Likely_benign]. Clinvar id is 2644179.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00135 (202/150010) while in subpopulation AMR AF= 0.00398 (60/15072). AF 95% confidence interval is 0.00317. There are 1 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.
• BS2: High AC in GnomAd at 202 AD gene.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 202 AN: 149928 Hom.: 1 Cov.: 28

Gnomad AFR AF: 0.000562

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.000578

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000417

Gnomad FIN AF: 0.000103

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00158

Gnomad OTH AF: 0.00340

GnomAD4 exome AF: 0.00186 AC: 1630 AN: 875378 Hom.: 6 Cov.: 12 AF XY: 0.00180 AC XY: 773 AN XY: 430112

Gnomad4 AFR exome AF: 0.000553

Gnomad4 AMR exome AF: 0.00320

Gnomad4 ASJ exome AF: 0.000617

Gnomad4 EAS exome AF: 0.0000722

Gnomad4 SAS exome AF: 0.000438

Gnomad4 FIN exome AF: 0.000325

Gnomad4 NFE exome AF: 0.00213

Gnomad4 OTH exome AF: 0.00188

GnomAD4 genome AF: 0.00135 AC: 202 AN: 150010 Hom.: 1 Cov.: 28 AF XY: 0.00130 AC XY: 95 AN XY: 73068

Gnomad4 AFR AF: 0.000560

Gnomad4 AMR AF: 0.00398

Gnomad4 ASJ AF: 0.000578

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000419

Gnomad4 FIN AF: 0.000103

Gnomad4 NFE AF: 0.00158

Gnomad4 OTH AF: 0.00337

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

Nov 01, 2022

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;