14-36520105-C-A

Variant names:

• chr14-36520105-C-A
• NM_001079668.3:c.25G>T

Variant summary

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

The NM_001079668.3(NKX2-1):​c.25G>T​(p.Ala9Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,918 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A9A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NKX2-1 NM_001079668.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.163

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:):

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

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX2-1	NM_001079668.3	c.25G>T	p.Ala9Ser	missense_variant	Exon 1 of 3	ENST00000354822.7	NP_001073136.1
NKX2-1-AS1	NR_103710.1	n.402+426C>A		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKX2-1	ENST00000354822.7	c.25G>T	p.Ala9Ser	missense_variant	Exon 1 of 3	1	NM_001079668.3	ENSP00000346879.6
SFTA3	ENST00000546983.2	n.-14+452G>T		intron_variant	Intron 1 of 3	4		ENSP00000449302.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460918 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726804

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 20, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Benign	0.079
Eigen_PC	Benign	0.056
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.50	T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Uncertain	0.44	T;T
MetaSVM	Uncertain	0.35	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.19	N;D
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D;.
Sift4G	Benign	0.55	T;.
Polyphen		0.76	P;.
Vest4		0.21
MutPred		0.22		Gain of phosphorylation at A9 (P = 0.0037);Gain of phosphorylation at A9 (P = 0.0037);
MVP		0.87
ClinPred		0.97	D
GERP RS		2.9
gMVP		0.075

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: chr14-36989310;