NM_001079668.3:c.-85G>T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 16 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:):

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKX2-1	NM_001079668.3	MANE Select	c.-85G>T		5_prime_UTR	Exon 1 of 3	NP_001073136.1	P43699-3
	NKX2-1-AS1	NR_103710.1		n.402+535C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKX2-1	ENST00000354822.7	TSL:1 MANE Select	c.-85G>T		5_prime_UTR	Exon 1 of 3	ENSP00000346879.6	P43699-3
	NKX2-1	ENST00000522719.4	TSL:1	c.-320G>T		5_prime_UTR	Exon 2 of 5	ENSP00000429519.4	P43699-1
	SFTA3	ENST00000546983.2	TSL:4	n.-14+343G>T		intron	N/A	ENSP00000449302.2	F8VVG2

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

African (AFR) AF: 0.0175 AC: 568 AN: 32398

American (AMR) AF: 0.243 AC: 9440 AN: 38908

Ashkenazi Jewish (ASJ) AF: 0.0585 AC: 1489 AN: 25444

East Asian (EAS) AF: 0.234 AC: 8661 AN: 37054

South Asian (SAS) AF: 0.0818 AC: 6669 AN: 81492

European-Finnish (FIN) AF: 0.0743 AC: 3231 AN: 43470

Middle Eastern (MID) AF: 0.0337 AC: 192 AN: 5690

European-Non Finnish (NFE) AF: 0.0665 AC: 72656 AN: 1093134

Other (OTH) AF: 0.0758 AC: 4460 AN: 58864

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

African (AFR) AF: 0.0237 AC: 986 AN: 41560

American (AMR) AF: 0.172 AC: 2629 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0475 AC: 165 AN: 3472

East Asian (EAS) AF: 0.220 AC: 1126 AN: 5126

South Asian (SAS) AF: 0.0901 AC: 435 AN: 4828

European-Finnish (FIN) AF: 0.0806 AC: 855 AN: 10606

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0621 AC: 4225 AN: 68004

Other (OTH) AF: 0.0719 AC: 152 AN: 2114

Alfa AF: 0.0645 Hom.: 831

Bravo AF: 0.0754

Asia WGS AF: 0.142 AC: 493 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Benign hereditary chorea (1)
-	-	1	Brain-lung-thyroid syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	15
DANN	Benign	0.92
PhyloP100		0.50
PromoterAI		-0.057	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

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