chr14-36517068-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001079668.3(NKX2-1):c.*210T>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 0.67 in 783,792 control chromosomes in the GnomAD database, including 163,521 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.66 ( 28343 hom., cov: 29)

Exomes 𝑓: 0.67 ( 135178 hom. )

Consequence

NKX2-1
NM_001079668.3 3_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.620

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 14-36517068-A-T is Benign according to our data. Variant chr14-36517068-A-T is described in ClinVar as [Benign]. Clinvar id is 313133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.766 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
NKX2-1	NM_001079668.3 link	c.*210T>A	3_prime_UTR_variant	Exon 3 of 3	ENST00000354822.7	NP_001073136.1	P43699-3
NKX2-1	NM_003317.4 link	c.*210T>A	3_prime_UTR_variant	Exon 2 of 2		NP_003308.1	P43699-1
SFTA3	NR_161364.1 link	n.89+2400T>A	intron_variant	Intron 1 of 4
SFTA3	NR_161365.1 link	n.89+2400T>A	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.*210T>A		3_prime_UTR_variant	Exon 3 of 3	1	NM_001079668.3	ENSP00000346879.6		P43699-3
SFTA3	ENST00000546983.2 link	n.373+1917T>A		intron_variant	Intron 2 of 3	4		ENSP00000449302.2		F8VVG2

Frequencies

GnomAD3 genomes

AF:

0.662

AC:

91636

AN:

138404

Hom.:

28337

Cov.:

show subpopulations

Gnomad AFR

AF:

0.555

Gnomad AMI

AF:

0.661

Gnomad AMR

AF:

0.618

Gnomad ASJ

AF:

0.636

Gnomad EAS

AF:

0.756

Gnomad SAS

AF:

0.787

Gnomad FIN

AF:

0.732

Gnomad MID

AF:

0.773

Gnomad NFE

AF:

0.715

Gnomad OTH

AF:

0.662

GnomAD4 exome

AF:

0.672

AC:

433646

AN:

645296

Hom.:

135178

Cov.:

AF XY:

0.672

AC XY:

215810

AN XY:

320954

show subpopulations

African (AFR)

AF:

0.560

AC:

8431

AN:

15066

American (AMR)

AF:

0.558

AC:

6139

AN:

11004

Ashkenazi Jewish (ASJ)

AF:

0.589

AC:

7158

AN:

12146

East Asian (EAS)

AF:

0.686

AC:

16548

AN:

24110

South Asian (SAS)

AF:

0.753

AC:

27577

AN:

36646

European-Finnish (FIN)

AF:

0.684

AC:

15921

AN:

23272

Middle Eastern (MID)

AF:

0.686

AC:

1445

AN:

2106

European-Non Finnish (NFE)

AF:

0.674

AC:

330809

AN:

491102

Other (OTH)

AF:

0.657

AC:

19618

AN:

29844

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

7054

14107

21161

28214

35268

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.662

AC:

91667

AN:

138496

Hom.:

28343

Cov.:

AF XY:

0.661

AC XY:

44477

AN XY:

67262

show subpopulations

African (AFR)

AF:

0.555

AC:

22124

AN:

39866

American (AMR)

AF:

0.617

AC:

7967

AN:

12904

Ashkenazi Jewish (ASJ)

AF:

0.636

AC:

1970

AN:

3096

East Asian (EAS)

AF:

0.755

AC:

3662

AN:

4850

South Asian (SAS)

AF:

0.787

AC:

3581

AN:

4548

European-Finnish (FIN)

AF:

0.732

AC:

6500

AN:

8880

Middle Eastern (MID)

AF:

0.778

AC:

207

AN:

266

European-Non Finnish (NFE)

AF:

0.715

AC:

43874

AN:

61396

Other (OTH)

AF:

0.663

AC:

1260

AN:

1900

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.527

Heterozygous variant carriers

1716

3432

5147

6863

8579

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.604

Hom.:

2023

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 10, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Brain-lung-thyroid syndrome

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.93

(source)

DANN

Benign

0.51

PhyloP100

0.62

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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chr14-36517068-A-T

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