rs1555349214
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001079668.3(NKX2-1):c.646del(p.Leu216CysfsTer12) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
NKX2-1
NM_001079668.3 frameshift
NM_001079668.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.70
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 Pathogenic. Variant got 18 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. There are 36 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 14-36517837-AG-A is Pathogenic according to our data. Variant chr14-36517837-AG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NKX2-1 | NM_001079668.3 | c.646del | p.Leu216CysfsTer12 | frameshift_variant | 3/3 | ENST00000354822.7 | |
SFTA3 | NR_161364.1 | n.89+1630del | intron_variant, non_coding_transcript_variant | ||||
NKX2-1 | NM_003317.4 | c.556del | p.Leu186CysfsTer12 | frameshift_variant | 2/2 | ||
SFTA3 | NR_161365.1 | n.89+1630del | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NKX2-1 | ENST00000354822.7 | c.646del | p.Leu216CysfsTer12 | frameshift_variant | 3/3 | 1 | NM_001079668.3 | P4 | |
ENST00000634305.1 | n.322+69002del | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 12, 2016 | - - |
Neurodevelopmental disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Rare Disease Group, Clinical Genetics, Karolinska Institutet | Apr 09, 2019 | - - |
Benign hereditary chorea Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Jan 30, 2023 | - - |
Computational scores
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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