Genetic Variant NKX2-1:c.*303dupT (chr14-36516974-C-CA) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001079668.3(NKX2-1):c.*303dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 447,940 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000069 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

NKX2-1
NM_001079668.3 3_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.798

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:

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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
NKX2-1	NM_001079668.3 link	c.*303dupT	3_prime_UTR_variant	Exon 3 of 3	ENST00000354822.7	NP_001073136.1	P43699-3
NKX2-1	NM_003317.4 link	c.*303dupT	3_prime_UTR_variant	Exon 2 of 2		NP_003308.1	P43699-1
SFTA3	NR_161364.1 link	n.89+2493dupT	intron_variant	Intron 1 of 4
SFTA3	NR_161365.1 link	n.89+2493dupT	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.*303dupT		3_prime_UTR_variant	Exon 3 of 3	1	NM_001079668.3	ENSP00000346879.6		P43699-3
SFTA3	ENST00000546983.2 link	n.373+2010dupT		intron_variant	Intron 2 of 3	4		ENSP00000449302.2		F8VVG2

Frequencies

GnomAD3 genomes

AF:

0.00000691

AC:

AN:

144650

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000157

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000132

AC:

AN:

303290

Hom.:

Cov.:

AF XY:

0.0000128

AC XY:

AN XY:

155958

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

8848

American (AMR)

AF:

0.00

AC:

AN:

9844

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10282

East Asian (EAS)

AF:

0.00

AC:

AN:

18540

South Asian (SAS)

AF:

0.0000308

AC:

AN:

32456

European-Finnish (FIN)

AF:

0.0000764

AC:

AN:

13084

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1334

European-Non Finnish (NFE)

AF:

0.0000105

AC:

AN:

190820

Other (OTH)

AF:

0.00

AC:

AN:

18082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000691

AC:

AN:

144650

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

70440

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

41080

American (AMR)

AF:

0.00

AC:

AN:

14240

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3214

East Asian (EAS)

AF:

0.00

AC:

AN:

5104

South Asian (SAS)

AF:

0.00

AC:

AN:

4650

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9752

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000157

AC:

AN:

63522

Other (OTH)

AF:

0.00

AC:

AN:

1968

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.80

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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14-36516974-CA-CAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over