rs137852692

Positions:

• chr14-36517781-C-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_001079668.3(NKX2-1):​c.703G>T​(p.Val235Phe) variant causes a missense 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V235A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NKX2-1 NM_001079668.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.73

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001079668.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-36517780-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2506929.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 14-36517781-C-A is Pathogenic according to our data. Variant chr14-36517781-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 8976.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NKX2-1	NM_001079668.3	c.703G>T	p.Val235Phe	missense_variant	3/3	ENST00000354822.7
SFTA3	NR_161364.1	n.89+1687G>T		intron_variant, non_coding_transcript_variant
NKX2-1	NM_003317.4	c.613G>T	p.Val205Phe	missense_variant	2/2
SFTA3	NR_161365.1	n.89+1687G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NKX2-1	ENST00000354822.7	c.703G>T	p.Val235Phe	missense_variant	3/3	1	NM_001079668.3	P4
	ENST00000634305.1	n.322+68944C>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Brain-lung-thyroid syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D;.;D;D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H;.;H;H
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.7	D;D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.057	B;B;B;B
Vest4		0.96
MutPred		0.96		Loss of MoRF binding (P = 0.0995);.;Loss of MoRF binding (P = 0.0995);Loss of MoRF binding (P = 0.0995);
MVP		0.90
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.99
gMVP		0.99

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

Other links and lift over

dbSNP: rs137852692; hg19: chr14-36986986;