rs137852694
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_001079668.3(NKX2-1):c.745C>T(p.Gln249*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
NKX2-1
NM_001079668.3 stop_gained
NM_001079668.3 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 7.91
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.382 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 14-36517739-G-A is Pathogenic according to our data. Variant chr14-36517739-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 8980.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NKX2-1 | NM_001079668.3 | c.745C>T | p.Gln249* | stop_gained | 3/3 | ENST00000354822.7 | NP_001073136.1 | |
NKX2-1 | NM_003317.4 | c.655C>T | p.Gln219* | stop_gained | 2/2 | NP_003308.1 | ||
SFTA3 | NR_161364.1 | n.89+1729C>T | intron_variant | |||||
SFTA3 | NR_161365.1 | n.89+1729C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NKX2-1 | ENST00000354822.7 | c.745C>T | p.Gln249* | stop_gained | 3/3 | 1 | NM_001079668.3 | ENSP00000346879.6 | ||
SFTA3 | ENST00000546983.2 | n.373+1246C>T | intron_variant | 4 | ENSP00000449302.2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1458130Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 725148
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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1458130
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32
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0
AN XY:
725148
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GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 23, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the NKX2-1 protein in which other variant(s) (p.Ala306Argfs*133) have been determined to be pathogenic (PMID: 28503612). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 8980). This premature translational stop signal has been observed in individual(s) with benign hereditary chorea (PMID: 16220345). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln249*) in the NKX2-1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 153 amino acid(s) of the NKX2-1 protein. - |
Benign hereditary chorea Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2005 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;A;A
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at