Genetic Variant NKX2-1:c.*460delT (chr14-36516817-CA-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001079668.3(NKX2-1):c.*460delT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.12 ( 1408 hom., cov: 0)

Exomes 𝑓: 0.19 ( 32 hom. )

Consequence

NKX2-1
NM_001079668.3 3_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -1.44

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:

SFTA3 (HGNC:18387): (surfactant associated 3) Involved in wound healing. Located in cytoplasm and extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

SFTA3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.265 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
NKX2-1	NM_001079668.3 link	c.*460delT	3_prime_UTR_variant	Exon 3 of 3	ENST00000354822.7	NP_001073136.1	P43699-3
NKX2-1	NM_003317.4 link	c.*460delT	3_prime_UTR_variant	Exon 2 of 2		NP_003308.1	P43699-1
SFTA3	NR_161364.1 link	n.89+2650delT	intron_variant	Intron 1 of 4
SFTA3	NR_161365.1 link	n.89+2650delT	intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKX2-1	ENST00000354822.7 link	c.*460delT		3_prime_UTR_variant	Exon 3 of 3	1	NM_001079668.3	ENSP00000346879.6		P43699-3
SFTA3	ENST00000546983.2 link	n.373+2167delT		intron_variant	Intron 2 of 3	4		ENSP00000449302.2		F8VVG2

Frequencies

GnomAD3 genomes

AF:

0.123

AC:

17430

AN:

142196

Hom.:

1398

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0485

Gnomad AMI

AF:

0.0930

Gnomad AMR

AF:

0.253

Gnomad ASJ

AF:

0.0969

Gnomad EAS

AF:

0.277

Gnomad SAS

AF:

0.183

Gnomad FIN

AF:

0.160

Gnomad MID

AF:

0.0445

Gnomad NFE

AF:

0.118

Gnomad OTH

AF:

0.112

GnomAD4 exome

AF:

0.194

AC:

13891

AN:

71702

Hom.:

Cov.:

AF XY:

0.191

AC XY:

6304

AN XY:

32964

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.173

AC:

574

AN:

3318

American (AMR)

AF:

0.275

AC:

610

AN:

2216

Ashkenazi Jewish (ASJ)

AF:

0.165

AC:

744

AN:

4512

East Asian (EAS)

AF:

0.287

AC:

2952

AN:

10294

South Asian (SAS)

AF:

0.245

AC:

161

AN:

656

European-Finnish (FIN)

AF:

0.179

AC:

AN:

Middle Eastern (MID)

AF:

0.149

AC:

AN:

430

European-Non Finnish (NFE)

AF:

0.174

AC:

7699

AN:

44210

Other (OTH)

AF:

0.179

AC:

1072

AN:

5982

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.389

Heterozygous variant carriers

502

1004

1506

2008

2510

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.123

AC:

17470

AN:

142256

Hom.:

1408

Cov.:

AF XY:

0.129

AC XY:

8883

AN XY:

68814

show subpopulations

African (AFR)

AF:

0.0489

AC:

1845

AN:

37716

American (AMR)

AF:

0.254

AC:

3685

AN:

14498

Ashkenazi Jewish (ASJ)

AF:

0.0969

AC:

324

AN:

3344

East Asian (EAS)

AF:

0.278

AC:

1363

AN:

4910

South Asian (SAS)

AF:

0.183

AC:

808

AN:

4404

European-Finnish (FIN)

AF:

0.160

AC:

1405

AN:

8764

Middle Eastern (MID)

AF:

0.0444

AC:

AN:

270

European-Non Finnish (NFE)

AF:

0.118

AC:

7721

AN:

65484

Other (OTH)

AF:

0.113

AC:

225

AN:

1984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

708

1416

2123

2831

3539

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0482

Hom.:

504

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Brain-lung-thyroid syndrome

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Benign hereditary chorea

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-1.4

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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14-36516817-CA-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over