14-36520077-C-A

Position:

• chr14-36520077-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001079668.3(NKX2-1):​c.53G>T​(p.Gly18Val) 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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NKX2-1 NM_001079668.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.23

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]

SFTA3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34420937).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NKX2-1	NM_001079668.3	c.53G>T	p.Gly18Val	missense_variant	1/3	ENST00000354822.7	NP_001073136.1
NKX2-1-AS1	NR_103710.1	n.402+398C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NKX2-1	ENST00000354822.7	c.53G>T	p.Gly18Val	missense_variant	1/3	1	NM_001079668.3	ENSP00000346879.6
SFTA3	ENST00000546983.2	n.-14+480G>T		intron_variant		4		ENSP00000449302.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

GeneDx

Mar 08, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Benign	-0.10
Eigen_PC	Benign	0.012
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.54	T;T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Uncertain	-0.029	T
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.21	N;D
REVEL	Benign	0.28
Sift	Benign	0.054	T;.
Sift4G	Benign	0.081	T;.
Polyphen		0.0010	B;.
Vest4		0.54
MutPred		0.20		Gain of loop (P = 0.0013);Gain of loop (P = 0.0013);
MVP		0.85
ClinPred		0.97	D
GERP RS		2.8
gMVP		0.096

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-36989282;