rs2076751

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_001079668.3(NKX2-1):c.-85G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0752 in 1,568,666 control chromosomes in the GnomAD database, including 6,050 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.070 ( 589 hom., cov: 32)

Exomes 𝑓: 0.076 ( 5461 hom. )

Consequence

NKX2-1
NM_001079668.3 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.502

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:

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

NKX2-1-AS1 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 14-36520214-C-A is Benign according to our data. Variant chr14-36520214-C-A is described in ClinVar as [Benign]. Clinvar id is 313149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NKX2-1	NM_001079668.3 linkuse as main transcript	c.-85G>T		5_prime_UTR_variant	1/3	ENST00000354822.7
NKX2-1-AS1	NR_103710.1 linkuse as main transcript	n.402+535C>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.-85G>T	5_prime_UTR_variant	1/3	1	NM_001079668.3	P4	P43699-3
NKX2-1-AS1	ENST00000521292.2 linkuse as main transcript	n.402+535C>A	intron_variant, non_coding_transcript_variant		2
	ENST00000634305.1 linkuse as main transcript	n.322+71377C>A	intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0697

AC:

10597

AN:

152094

Hom.:

581

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0237

Gnomad AMI

AF:

0.0471

Gnomad AMR

AF:

0.171

Gnomad ASJ

AF:

0.0475

Gnomad EAS

AF:

0.219

Gnomad SAS

AF:

0.0900

Gnomad FIN

AF:

0.0806

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0621

Gnomad OTH

AF:

0.0717

GnomAD4 exome

AF:

0.0758

AC:

107366

AN:

1416454

Hom.:

5461

Cov.:

AF XY:

0.0755

AC XY:

52973

AN XY:

701522

show subpopulations

Gnomad4 AFR exome

AF:

0.0175

Gnomad4 AMR exome

AF:

0.243

Gnomad4 ASJ exome

AF:

0.0585

Gnomad4 EAS exome

AF:

0.234

Gnomad4 SAS exome

AF:

0.0818

Gnomad4 FIN exome

AF:

0.0743

Gnomad4 NFE exome

AF:

0.0665

Gnomad4 OTH exome

AF:

0.0758

GnomAD4 genome

AF:

0.0698

AC:

10621

AN:

152212

Hom.:

589

Cov.:

AF XY:

0.0740

AC XY:

5504

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.0237

Gnomad4 AMR

AF:

0.172

Gnomad4 ASJ

AF:

0.0475

Gnomad4 EAS

AF:

0.220

Gnomad4 SAS

AF:

0.0901

Gnomad4 FIN

AF:

0.0806

Gnomad4 NFE

AF:

0.0621

Gnomad4 OTH

AF:

0.0719

Alfa

AF:

0.0628

Hom.:

466

Bravo

AF:

0.0754

Asia WGS

AF:

0.142

AC:

493

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Brain-lung-thyroid syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 11, 2018

- -

Benign hereditary chorea

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.92

Splicing

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