rs1555349218

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_001079668.3(NKX2-1):​c.635A>C​(p.Gln212Pro) variant causes a missense change. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)

Consequence

NKX2-1
NM_001079668.3 missense

Scores

14
4
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 6.09
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001079668.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.925
PP5
Variant 14-36517849-T-G is Pathogenic according to our data. Variant chr14-36517849-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 436016.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NKX2-1NM_001079668.3 linkuse as main transcriptc.635A>C p.Gln212Pro missense_variant 3/3 ENST00000354822.7
SFTA3NR_161364.1 linkuse as main transcriptn.89+1619A>C intron_variant, non_coding_transcript_variant
NKX2-1NM_003317.4 linkuse as main transcriptc.545A>C p.Gln182Pro missense_variant 2/2
SFTA3NR_161365.1 linkuse as main transcriptn.89+1619A>C intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NKX2-1ENST00000354822.7 linkuse as main transcriptc.635A>C p.Gln212Pro missense_variant 3/31 NM_001079668.3 P4P43699-3
ENST00000634305.1 linkuse as main transcriptn.322+69012T>G intron_variant, non_coding_transcript_variant 5

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Brain-lung-thyroid syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoJun 27, 2016- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJun 01, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.33
CADD
Pathogenic
29
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.76
D;.;D;D
Eigen
Pathogenic
0.74
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.94
.;D;.;D
M_CAP
Pathogenic
0.94
D
MetaRNN
Pathogenic
0.92
D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.1
M;.;M;M
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.92
D
PROVEAN
Pathogenic
-5.7
D;D;D;D
REVEL
Pathogenic
0.92
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
1.0
D;D;D;D
Vest4
0.90
MutPred
0.45
Loss of MoRF binding (P = 0.0488);.;Loss of MoRF binding (P = 0.0488);Loss of MoRF binding (P = 0.0488);
MVP
0.95
ClinPred
1.0
D
GERP RS
4.4
Varity_R
0.99
gMVP
0.96

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555349218; hg19: chr14-36987054; API