14-36517069-A-T

Position:

chr14-36517069-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001079668.3(NKX2-1):c.*209T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00351 in 834,346 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0031 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0036 ( 6 hom. )

Consequence

NKX2-1
NM_001079668.3 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.00700

Variant links:

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 14-36517069-A-T is Benign according to our data. Variant chr14-36517069-A-T is described in ClinVar as [Benign]. Clinvar id is 313134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00308 (461/149550) while in subpopulation AFR AF= 0.00801 (327/40816). AF 95% confidence interval is 0.0073. There are 3 homozygotes in gnomad4. There are 231 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 461 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE
NKX2-1	NM_001079668.3 linkuse as main transcript	c.*209T>A	3_prime_UTR_variant	3/3	ENST00000354822.7
SFTA3	NR_161364.1 linkuse as main transcript	n.89+2399T>A	intron_variant, non_coding_transcript_variant
NKX2-1	NM_003317.4 linkuse as main transcript	c.*209T>A	3_prime_UTR_variant	2/2
SFTA3	NR_161365.1 linkuse as main transcript	n.89+2399T>A	intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NKX2-1	ENST00000354822.7 linkuse as main transcript	c.*209T>A	3_prime_UTR_variant	3/3	1	NM_001079668.3	P4	P43699-3
NKX2-1	ENST00000498187.6 linkuse as main transcript	c.*209T>A	3_prime_UTR_variant	2/2	1		A1	P43699-1
	ENST00000634305.1 linkuse as main transcript	n.322+68232A>T	intron_variant, non_coding_transcript_variant		5
NKX2-1	ENST00000518149.5 linkuse as main transcript	c.*209T>A	3_prime_UTR_variant	3/3	5		A1	P43699-1

Frequencies

GnomAD3 genomes

AF:

0.00304

AC:

455

AN:

149440

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00791

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00128

Gnomad ASJ

AF:

0.000291

Gnomad EAS

AF:

0.00270

Gnomad SAS

AF:

0.00612

Gnomad FIN

AF:

0.00139

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000789

Gnomad OTH

AF:

0.00148

GnomAD4 exome

AF:

0.00360

AC:

2464

AN:

684796

Hom.:

Cov.:

AF XY:

0.00379

AC XY:

1282

AN XY:

338626

show subpopulations

Gnomad4 AFR exome

AF:

0.0109

Gnomad4 AMR exome

AF:

0.00352

Gnomad4 ASJ exome

AF:

0.00129

Gnomad4 EAS exome

AF:

0.00371

Gnomad4 SAS exome

AF:

0.0115

Gnomad4 FIN exome

AF:

0.00295

Gnomad4 NFE exome

AF:

0.00292

Gnomad4 OTH exome

AF:

0.00364

GnomAD4 genome

AF:

0.00308

AC:

461

AN:

149550

Hom.:

Cov.:

AF XY:

0.00317

AC XY:

231

AN XY:

72972

show subpopulations

Gnomad4 AFR

AF:

0.00801

Gnomad4 AMR

AF:

0.00127

Gnomad4 ASJ

AF:

0.000291

Gnomad4 EAS

AF:

0.00271

Gnomad4 SAS

AF:

0.00612

Gnomad4 FIN

AF:

0.00139

Gnomad4 NFE

AF:

0.000789

Gnomad4 OTH

AF:

0.00196

Alfa

AF:

0.00175

Hom.:

Bravo

AF:

0.00317

Asia WGS

AF:

0.0100

AC:

AN:

3470

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	NKX2-1: BS1, BS2 -

Brain-lung-thyroid syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Benign hereditary chorea

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.37

DANN

Benign

0.55

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over