Genetic Variant NKX2-1:c.*217dupA (chr14-36517060-C-CT) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBA1

The NM_001079668.3(NKX2-1):c.*217dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 767,596 control chromosomes in the GnomAD database, including 24,439 homozygotes. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.27 ( 6267 hom., cov: 21)

Exomes 𝑓: 0.27 ( 18172 hom. )

Consequence

NKX2-1
NM_001079668.3 3_prime_UTR

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.476

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 -10 ACMG points.

BP6

Variant 14-36517060-C-CT is Benign according to our data. Variant chr14-36517060-C-CT is described in ClinVar as [Benign]. Clinvar id is 1287959.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.404 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
NKX2-1	NM_001079668.3 link	c.*217dupA	3_prime_UTR_variant	Exon 3 of 3	ENST00000354822.7	NP_001073136.1	P43699-3
NKX2-1	NM_003317.4 link	c.*217dupA	3_prime_UTR_variant	Exon 2 of 2		NP_003308.1	P43699-1
SFTA3	NR_161364.1 link	n.89+2407dupA	intron_variant	Intron 1 of 4
SFTA3	NR_161365.1 link	n.89+2407dupA	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.*217dupA		3_prime_UTR_variant	Exon 3 of 3	1	NM_001079668.3	ENSP00000346879.6		P43699-3
SFTA3	ENST00000546983.2 link	n.373+1924dupA		intron_variant	Intron 2 of 3	4		ENSP00000449302.2		F8VVG2

Frequencies

GnomAD3 genomes

AF:

0.268

AC:

39599

AN:

147790

Hom.:

6260

Cov.:

show subpopulations

Gnomad AFR

AF:

0.103

Gnomad AMI

AF:

0.408

Gnomad AMR

AF:

0.412

Gnomad ASJ

AF:

0.354

Gnomad EAS

AF:

0.275

Gnomad SAS

AF:

0.234

Gnomad FIN

AF:

0.287

Gnomad MID

AF:

0.253

Gnomad NFE

AF:

0.328

Gnomad OTH

AF:

0.299

GnomAD4 exome

AF:

0.265

AC:

164336

AN:

619706

Hom.:

18172

Cov.:

AF XY:

0.267

AC XY:

82793

AN XY:

310382

show subpopulations

African (AFR)

AF:

0.0792

AC:

1333

AN:

16836

American (AMR)

AF:

0.369

AC:

4690

AN:

12706

Ashkenazi Jewish (ASJ)

AF:

0.307

AC:

3823

AN:

12446

East Asian (EAS)

AF:

0.276

AC:

7027

AN:

25442

South Asian (SAS)

AF:

0.203

AC:

8028

AN:

39460

European-Finnish (FIN)

AF:

0.263

AC:

6192

AN:

23544

Middle Eastern (MID)

AF:

0.233

AC:

498

AN:

2134

European-Non Finnish (NFE)

AF:

0.273

AC:

124876

AN:

457670

Other (OTH)

AF:

0.267

AC:

7869

AN:

29468

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

4495

8990

13485

17980

22475

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.268

AC:

39612

AN:

147890

Hom.:

6267

Cov.:

AF XY:

0.271

AC XY:

19432

AN XY:

71712

show subpopulations

African (AFR)

AF:

0.103

AC:

4164

AN:

40606

American (AMR)

AF:

0.413

AC:

6142

AN:

14876

Ashkenazi Jewish (ASJ)

AF:

0.354

AC:

1217

AN:

3438

East Asian (EAS)

AF:

0.275

AC:

1394

AN:

5066

South Asian (SAS)

AF:

0.234

AC:

1090

AN:

4664

European-Finnish (FIN)

AF:

0.287

AC:

2616

AN:

9106

Middle Eastern (MID)

AF:

0.245

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.328

AC:

21944

AN:

66902

Other (OTH)

AF:

0.298

AC:

613

AN:

2058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

1141

2282

3423

4564

5705

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.104

Hom.:

200

Asia WGS

AF:

0.258

AC:

897

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Aug 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.48

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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14-36517060-C-CT

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