14-36517900-C-T

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.584G>A(p.Arg195Gln) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R195W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NKX2-1 NM_001079668.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 5.98

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 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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 chr14-36517901-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 992992.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 14-36517900-C-T is Pathogenic according to our data. Variant chr14-36517900-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 505233.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NKX2-1	NM_001079668.3	c.584G>A	p.Arg195Gln	missense_variant	3/3	ENST00000354822.7
SFTA3	NR_161364.1	n.89+1568G>A		intron_variant, non_coding_transcript_variant
NKX2-1	NM_003317.4	c.494G>A	p.Arg165Gln	missense_variant	2/2
SFTA3	NR_161365.1	n.89+1568G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NKX2-1	ENST00000354822.7	c.584G>A	p.Arg195Gln	missense_variant	3/3	1	NM_001079668.3	P4
	ENST00000634305.1	n.322+69063C>T		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:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 19, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg195 amino acid residue in NKX2-1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20020530, 23430038). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 505233). This missense change has been observed in individual(s) with clinical features of NKX2-1-related conditions (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 195 of the NKX2-1 protein (p.Arg195Gln). -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 20, 2016

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg195Gln variant in NKX2-1 has not been previously reported in individuals with pulmonar y disease or in large population studies. However, a variant at the same codon ( p.Arg195Trp, c.583C>T) has been identified de novo in two individuals with featu res consistent with Brain-Lung-Thyroid syndrome (Guillot 2009, listed as p.Arg16 5Trp and Hamvas 2013). The p.Arg195Gln variant is located in the DNA binding dom ain of the NKX2-1 transcription factor and the affected amino acid is conserved in evolution, increasing the likelihood that the variant affects protein functio n. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Arg195Gln variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D;.;D;D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H;.;H;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.8	D;D;D;D
REVEL	Pathogenic	0.99
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.96
MutPred		0.94		Loss of MoRF binding (P = 0.0735);.;Loss of MoRF binding (P = 0.0735);Loss of MoRF binding (P = 0.0735);
MVP		0.95
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.90
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1555349228; hg19: chr14-36987105;