14-36517068-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001079668.3(NKX2-1):c.*210T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.67 in 783,792 control chromosomes in the GnomAD database, including 163,521 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (28343 hom., cov: 29)
  • Exomes 𝑓: 0.67 (135178 hom.)
• Consequence: NKX2-1 NM_001079668.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.620

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 14-36517068-A-T is Benign according to our data. Variant chr14-36517068-A-T is described in ClinVar as [Benign]. Clinvar id is 313133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.766 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NKX2-1	NM_001079668.3	c.*210T>A		3_prime_UTR_variant	3/3	ENST00000354822.7
SFTA3	NR_161364.1	n.89+2400T>A		intron_variant, non_coding_transcript_variant
NKX2-1	NM_003317.4	c.*210T>A		3_prime_UTR_variant	2/2
SFTA3	NR_161365.1	n.89+2400T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NKX2-1	ENST00000354822.7	c.*210T>A		3_prime_UTR_variant	3/3	1	NM_001079668.3	P4
NKX2-1	ENST00000498187.6	c.*210T>A		3_prime_UTR_variant	2/2	1		A1
	ENST00000634305.1	n.322+68231A>T		intron_variant, non_coding_transcript_variant		5
NKX2-1	ENST00000518149.5	c.*210T>A		3_prime_UTR_variant	3/3	5		A1

Frequencies

GnomAD3 genomes AF: 0.662 AC: 91636 AN: 138404 Hom.: 28337 Cov.: 29

Gnomad AFR AF: 0.555

Gnomad AMI AF: 0.661

Gnomad AMR AF: 0.618

Gnomad ASJ AF: 0.636

Gnomad EAS AF: 0.756

Gnomad SAS AF: 0.787

Gnomad FIN AF: 0.732

Gnomad MID AF: 0.773

Gnomad NFE AF: 0.715

Gnomad OTH AF: 0.662

GnomAD4 exome AF: 0.672 AC: 433646 AN: 645296 Hom.: 135178 Cov.: 10 AF XY: 0.672 AC XY: 215810 AN XY: 320954

Gnomad4 AFR exome AF: 0.560

Gnomad4 AMR exome AF: 0.558

Gnomad4 ASJ exome AF: 0.589

Gnomad4 EAS exome AF: 0.686

Gnomad4 SAS exome AF: 0.753

Gnomad4 FIN exome AF: 0.684

Gnomad4 NFE exome AF: 0.674

Gnomad4 OTH exome AF: 0.657

GnomAD4 genome AF: 0.662 AC: 91667 AN: 138496 Hom.: 28343 Cov.: 29 AF XY: 0.661 AC XY: 44477 AN XY: 67262

Gnomad4 AFR AF: 0.555

Gnomad4 AMR AF: 0.617

Gnomad4 ASJ AF: 0.636

Gnomad4 EAS AF: 0.755

Gnomad4 SAS AF: 0.787

Gnomad4 FIN AF: 0.732

Gnomad4 NFE AF: 0.715

Gnomad4 OTH AF: 0.663

Alfa AF: 0.604 Hom.: 2023

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brain-lung-thyroid syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 10, 2019

- -

Benign hereditary chorea Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.93
Dann	Benign	0.51

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: rs10139625; hg19: chr14-36986273;