rs28936672

chr14-36517771-C-Achr14-36517771-C-Gchr14-36517771-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001079668.3(NKX2-1):c.713G>T(p.Trp238Leu) 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. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W238S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NKX2-1 NM_001079668.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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 18 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, 1 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 chr14-36517771-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1685383.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 14-36517771-C-A is Pathogenic according to our data. Variant chr14-36517771-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8974.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.713G>T	p.Trp238Leu	missense_variant	3/3	ENST00000354822.7
SFTA3	NR_161364.1	n.89+1697G>T		intron_variant, non_coding_transcript_variant
NKX2-1	NM_003317.4	c.623G>T	p.Trp208Leu	missense_variant	2/2
SFTA3	NR_161365.1	n.89+1697G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NKX2-1	ENST00000354822.7	c.713G>T	p.Trp238Leu	missense_variant	3/3	1	NM_001079668.3	P4
	ENST00000634305.1	n.322+68934C>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2016	The W238L pathogenic variant in the NKX2-1 gene has been reported to segregate with disease in a large family with benign hereditary chorea. The W238L variant was not found in unaffected family members, and was also absent from 200 control chromosomes from the general population (Breedveld et al., 2002). The W238L variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The W238L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs within the functionally relevant homeobox DNA binding domain, at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (V235F, I237F, I237M, Q240P, R243S, R243P) have been reported in the Human Gene Mutation Database in association with NKX2-1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret W238L as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 04, 2021	This variant is not present in population databases (ExAC no frequency). This sequence change replaces tryptophan with leucine at codon 238 of the NKX2-1 protein (p.Trp238Leu). The tryptophan residue is highly conserved and there is a small physicochemical difference between tryptophan and leucine. This variant has been observed in individual(s) with benign hereditary chorea (PMID: 11971878). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8974). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. -

Brain-lung-thyroid syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Apr 11, 2016

- -

Benign hereditary chorea Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 15, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	33
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D;.;D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	4.2	H;.;H;H
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-12	D;D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.96
MutPred		0.97		Gain of disorder (P = 0.0223);.;Gain of disorder (P = 0.0223);Gain of disorder (P = 0.0223);
MVP		0.98
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.98
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs28936672; hg19: chr14-36986976;