rs2076751

Variant names:

• chr14-36520214-C-A
• rs2076751
• NM_001079668.3:c.-85G>T

Your query was ambiguous. Multiple possible variants found:

• chr14-36520214-C-A
• chr14-36520214-C-G
• chr14-36520214-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001079668.3(NKX2-1):​c.-85G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0752 in 1,568,666 control chromosomes in the GnomAD database, including 6,050 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.070 (589 hom., cov: 32)
  • Exomes 𝑓: 0.076 (5461 hom.)
• Consequence: NKX2-1 NM_001079668.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.502

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 Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 14-36520214-C-A is Benign according to our data. Variant chr14-36520214-C-A is described in ClinVar as [Benign]. Clinvar id is 313149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX2-1	NM_001079668.3	c.-85G>T		5_prime_UTR_variant	Exon 1 of 3	ENST00000354822.7	NP_001073136.1
NKX2-1-AS1	NR_103710.1	n.402+535C>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.-85G>T		5_prime_UTR_variant	Exon 1 of 3	1	NM_001079668.3	ENSP00000346879.6
SFTA3	ENST00000546983.2	n.-14+343G>T		intron_variant	Intron 1 of 3	4		ENSP00000449302.2

Frequencies

GnomAD3 genomes AF: 0.0697 AC: 10597 AN: 152094 Hom.: 581 Cov.: 32

Gnomad AFR AF: 0.0237

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.0475

Gnomad EAS AF: 0.219

Gnomad SAS AF: 0.0900

Gnomad FIN AF: 0.0806

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0621

Gnomad OTH AF: 0.0717

GnomAD4 exome AF: 0.0758 AC: 107366 AN: 1416454 Hom.: 5461 Cov.: 32 AF XY: 0.0755 AC XY: 52973 AN XY: 701522

Gnomad4 AFR exome AF: 0.0175

Gnomad4 AMR exome AF: 0.243

Gnomad4 ASJ exome AF: 0.0585

Gnomad4 EAS exome AF: 0.234

Gnomad4 SAS exome AF: 0.0818

Gnomad4 FIN exome AF: 0.0743

Gnomad4 NFE exome AF: 0.0665

Gnomad4 OTH exome AF: 0.0758

GnomAD4 genome AF: 0.0698 AC: 10621 AN: 152212 Hom.: 589 Cov.: 32 AF XY: 0.0740 AC XY: 5504 AN XY: 74396

Gnomad4 AFR AF: 0.0237

Gnomad4 AMR AF: 0.172

Gnomad4 ASJ AF: 0.0475

Gnomad4 EAS AF: 0.220

Gnomad4 SAS AF: 0.0901

Gnomad4 FIN AF: 0.0806

Gnomad4 NFE AF: 0.0621

Gnomad4 OTH AF: 0.0719

Alfa AF: 0.0628 Hom.: 466

Bravo AF: 0.0754

Asia WGS AF: 0.142 AC: 493 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Brain-lung-thyroid syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Benign hereditary chorea Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.44
CADD	Benign	15
DANN	Benign	0.92

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2076751; hg19: chr14-36989419; COSMIC: COSV105906463; COSMIC: COSV105906463;