14-36520101-C-T

Position:

chr14-36520101-C-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.29G>A(p.Arg10Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000529 in 1,613,170 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00053 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00053 ( 3 hom. )

Consequence

NKX2-1
NM_001079668.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.0360

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:

SFTA3 (HGNC:):

SFTA3 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 (MetaRNN=0.007312238).

BP6

Variant 14-36520101-C-T is Benign according to our data. Variant chr14-36520101-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 313147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-36520101-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000525 (80/152288) while in subpopulation AMR AF= 0.000392 (6/15308). AF 95% confidence interval is 0.00017. There are 1 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 80 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NKX2-1	NM_001079668.3 linkuse as main transcript	c.29G>A	p.Arg10Gln	missense_variant	1/3	ENST00000354822.7	NP_001073136.1	P43699-3
NKX2-1-AS1	NR_103710.1 linkuse as main transcript	n.402+422C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NKX2-1	ENST00000354822.7 linkuse as main transcript	c.29G>A	p.Arg10Gln	missense_variant	1/3	1	NM_001079668.3	ENSP00000346879.6		P43699-3
SFTA3	ENST00000546983.2 linkuse as main transcript	n.-14+456G>A		intron_variant		4		ENSP00000449302.2		F8VVG2

Frequencies

GnomAD3 genomes

AF:

0.000526

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.00102

AC:

244

AN:

239806

Hom.:

AF XY:

0.000896

AC XY:

118

AN XY:

131636

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000818

Gnomad ASJ exome

AF:

0.0183

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000230

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000188

Gnomad OTH exome

AF:

0.00170

GnomAD4 exome

AF:

0.000530

AC:

774

AN:

1460882

Hom.:

Cov.:

AF XY:

0.000508

AC XY:

369

AN XY:

726782

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00110

Gnomad4 ASJ exome

AF:

0.0159

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000255

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000176

Gnomad4 OTH exome

AF:

0.00139

GnomAD4 genome

AF:

0.000525

AC:

AN:

152288

Hom.:

Cov.:

AF XY:

0.000564

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.0161

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.00179

Hom.:

Bravo

AF:

0.000638

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000969

AC:

ExAC

AF:

0.000706

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Brain-lung-thyroid syndrome

Benign:2

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. -
Likely benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Apr 18, 2019	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2020	- -

NKX2-1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 25, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Benign hereditary chorea

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

1.0

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.34

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.65

T;T

M_CAP

Pathogenic

0.89

MetaRNN

Benign

0.0073

T;T

MetaSVM

Benign

-0.60

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.34

N;D

REVEL

Benign

0.18

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

0.0

B;.

Vest4

0.18

MVP

0.83

ClinPred

0.071

GERP RS

0.89

gMVP

0.16

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