rs587776709

Variant names:

• chr14-36519103-GC-G
• rs587776709
• NM_001079668.3:c.344delG

Your query was ambiguous. Multiple possible variants found:

• chr14-36519103-GC-G
• chr14-36519103-GC-GCC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001079668.3(NKX2-1):​c.344delG​(p.Gly115AlafsTer10) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NKX2-1 NM_001079668.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.69
• Publications: 5 publications found

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:):

SFTA3 (HGNC:18387): (surfactant associated 3) Involved in wound healing. Located in cytoplasm and extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

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

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-36519103-GC-G is Pathogenic according to our data. Variant chr14-36519103-GC-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 807109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001079668.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKX2-1	NM_001079668.3	MANE Select	c.344delG	p.Gly115AlafsTer10	frameshift	Exon 2 of 3	NP_001073136.1
	NKX2-1	NM_003317.4		c.254delG	p.Gly85AlafsTer10	frameshift	Exon 1 of 2	NP_003308.1
	SFTA3	NR_161364.1		n.89+364delG		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKX2-1	ENST00000354822.7	TSL:1 MANE Select	c.344delG	p.Gly115AlafsTer10	frameshift	Exon 2 of 3	ENSP00000346879.6
	NKX2-1	ENST00000498187.6	TSL:1	c.254delG	p.Gly85AlafsTer10	frameshift	Exon 1 of 2	ENSP00000429607.2
	NKX2-1	ENST00000522719.4	TSL:1	c.254delG	p.Gly85AlafsTer10	frameshift	Exon 4 of 5	ENSP00000429519.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000429 AC: 1 AN: 233094 AF XY: 0.00000776

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000939

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1451746 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 722638

African (AFR) AF: 0.00 AC: 0 AN: 33404

American (AMR) AF: 0.00 AC: 0 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 86092

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44668

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111302

Other (OTH) AF: 0.00 AC: 0 AN: 60154

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brain-lung-thyroid syndrome Pathogenic:2

Mar 20, 2020

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. This variant has been reported as pathogenic (ClinVar ID: VCV000807109, PMID:30746413). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000043). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

not provided Pathogenic:1

May 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587776709; hg19: chr14-36988308; COSMIC: COSV61388002; COSMIC: COSV61388002;