14-36519337-G-C

Position:

• chr14-36519337-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000354822.7(NKX2-1):​c.111C>G​(p.His37Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H37P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NKX2-1 ENST00000354822.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.36

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]

NKX2-1-AS1 (HGNC:40585): (NKX2-1 antisense RNA 1)

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21948099).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NKX2-1	NM_001079668.3	c.111C>G	p.His37Gln	missense_variant	2/3	ENST00000354822.7	NP_001073136.1
NKX2-1-AS1	NR_103710.1	n.60G>C		non_coding_transcript_exon_variant	1/2
SFTA3	NR_161364.1	n.89+131C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NKX2-1	ENST00000354822.7	c.111C>G	p.His37Gln	missense_variant	2/3	1	NM_001079668.3	ENSP00000346879	P4
NKX2-1-AS1	ENST00000521292.2	n.60G>C		non_coding_transcript_exon_variant	1/2	2
	ENST00000634305.1	n.322+70500G>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 06, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 tolerated. This variant has not been reported in the literature in individuals affected with NKX2-1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 37 of the NKX2-1 protein (p.His37Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.36	T;.;T;T
Eigen	Benign	-0.017
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	.;D;.;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.9	L;.;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.96	D
PROVEAN	Uncertain	-4.2	D;D;D;D
REVEL	Benign	0.21
Sift	Benign	0.10	T;T;T;T
Sift4G	Benign	0.20	T;T;T;T
Polyphen		0.0040	B;B;B;B
Vest4		0.40
MutPred		0.15		Gain of glycosylation at P5 (P = 0.1402);.;Gain of glycosylation at P5 (P = 0.1402);Gain of glycosylation at P5 (P = 0.1402);
MVP		0.81
ClinPred		0.92	D
GERP RS		4.2
Varity_R		0.59
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs758847127; hg19: chr14-36988542;