Genetic Variant NKX2-1:c.-61C>T (chr14-36519418-G-A) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_003317.4(NKX2-1):c.-61C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00607 in 1,607,598 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0053 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0062 ( 47 hom. )

Consequence

NKX2-1
NM_003317.4 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.50

Publications

0 publications found

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:

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

NKX2-1-AS1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 14-36519418-G-A is Benign according to our data. Variant chr14-36519418-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1186928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00526 (801/152376) while in subpopulation SAS AF = 0.013 (63/4830). AF 95% confidence interval is 0.0105. There are 3 homozygotes in GnomAd4. There are 424 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 801 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003317.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NKX2-1	NM_001079668.3	MANE Select	c.78-48C>T	intron	N/A	NP_001073136.1	P43699-3
NKX2-1	NM_003317.4		c.-61C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 2	NP_003308.1	P43699-1
NKX2-1	NM_003317.4		c.-61C>T	5_prime_UTR	Exon 1 of 2	NP_003308.1	P43699-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NKX2-1	ENST00000498187.6	TSL:1	c.-61C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 2	ENSP00000429607.2	P43699-1
NKX2-1	ENST00000498187.6	TSL:1	c.-61C>T	5_prime_UTR	Exon 1 of 2	ENSP00000429607.2	P43699-1
NKX2-1	ENST00000354822.7	TSL:1 MANE Select	c.78-48C>T	intron	N/A	ENSP00000346879.6	P43699-3

Frequencies

GnomAD3 genomes

AF:

0.00526

AC:

801

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000964

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0130

Gnomad FIN

AF:

0.0130

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00704

Gnomad OTH

AF:

0.00716

GnomAD2 exomes

AF:

0.00632

AC:

1461

AN:

231156

AF XY:

0.00664

show subpopulations

Gnomad AFR exome

AF:

0.00132

Gnomad AMR exome

AF:

0.00176

Gnomad ASJ exome

AF:

0.00156

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0150

Gnomad NFE exome

AF:

0.00703

Gnomad OTH exome

AF:

0.00457

GnomAD4 exome

AF:

0.00615

AC:

8956

AN:

1455222

Hom.:

Cov.:

AF XY:

0.00619

AC XY:

4474

AN XY:

723228

show subpopulations

African (AFR)

AF:

0.000659

AC:

AN:

33378

American (AMR)

AF:

0.00181

AC:

AN:

44094

Ashkenazi Jewish (ASJ)

AF:

0.00181

AC:

AN:

26016

East Asian (EAS)

AF:

0.00

AC:

AN:

39606

South Asian (SAS)

AF:

0.0108

AC:

919

AN:

84906

European-Finnish (FIN)

AF:

0.0129

AC:

667

AN:

51732

Middle Eastern (MID)

AF:

0.00724

AC:

AN:

5662

European-Non Finnish (NFE)

AF:

0.00617

AC:

6848

AN:

1109668

Other (OTH)

AF:

0.00552

AC:

332

AN:

60160

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

524

1048

1573

2097

2621

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

260

520

780

1040

1300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00526

AC:

801

AN:

152376

Hom.:

Cov.:

AF XY:

0.00569

AC XY:

424

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.000962

AC:

AN:

41600

American (AMR)

AF:

0.00333

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.0130

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0130

AC:

138

AN:

10630

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00704

AC:

479

AN:

68034

Other (OTH)

AF:

0.00709

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

126

168

210

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00570

Hom.:

Bravo

AF:

0.00389

Asia WGS

AF:

0.00404

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.94

PhyloP100

2.5

PromoterAI

-0.013

Neutral

(source)

Mutation Taster

=299/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over