chr14-36517960-G-T

Position:

• chr14-36517960-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001079668.3(NKX2-1):​c.524C>A​(p.Ser175*) variant causes a stop gained 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NKX2-1 NM_001079668.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.08

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-36517960-G-T is Pathogenic according to our data. Variant chr14-36517960-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 217884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-36517960-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NKX2-1	NM_001079668.3	c.524C>A	p.Ser175*	stop_gained	3/3	ENST00000354822.7	NP_001073136.1
NKX2-1	NM_003317.4	c.434C>A	p.Ser145*	stop_gained	2/2		NP_003308.1
SFTA3	NR_161364.1	n.89+1508C>A		intron_variant
SFTA3	NR_161365.1	n.89+1508C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NKX2-1	ENST00000354822.7	c.524C>A	p.Ser175*	stop_gained	3/3	1	NM_001079668.3	ENSP00000346879.6
SFTA3	ENST00000546983.2	n.373+1025C>A		intron_variant		4		ENSP00000449302.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: 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	Oct 20, 2022	Reported in unrelated patients with benign hereditary chorea referred for genetic testing at GeneDx and in the published literature (Ferrara et al., 2008; Salvatore et al., 2010); Nonsense variant predicted to result in protein truncation, as the last 227 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Published functional studies demonstrate p.(S175*) renders the NKX2-1 protein unable to translocate into the nucleus (Ferrara et al., 2008); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24555207, 20544814, 18788921, 27066577) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 23, 2021	This sequence change creates a premature translational stop signal (p.Ser175*) in the NKX2-1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 227 amino acid(s) of the NKX2-1 protein. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects NKX2-1 function (PMID: 18788921). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 217884). This variant is also known as c.609C>A (p.S145X). This premature translational stop signal has been observed in individual(s) with NKX2-1 related conditions (PMID: 18788921, 27066577). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). -

Brain-lung-thyroid syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Mendelics

Aug 01, 2014

- -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Dec 20, 2021

ACMG categories: PVS1,PM2,PP5 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	40
DANN	Uncertain	0.99
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.97	D
Vest4		0.87
GERP RS		3.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs863225300; hg19: chr14-36987165;