14-36517067-TAA-TA

Variant names:

• chr14-36517067-TA-T
• rs886050480
• NM_001079668.3:c.*210delT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001079668.3(NKX2-1):​c.*210delT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 869,976 control chromosomes in the GnomAD database, including 3 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00046 (2 hom., cov: 29)
  • Exomes 𝑓: 0.0023 (1 hom.)
• Consequence: NKX2-1 NM_001079668.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.620
• Publications: 0 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]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000463 (67/144762) while in subpopulation AFR AF = 0.00116 (47/40384). AF 95% confidence interval is 0.000899. There are 2 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High AC in GnomAd4 at 67 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX2-1	NM_001079668.3	c.*210delT		3_prime_UTR_variant	Exon 3 of 3	ENST00000354822.7	NP_001073136.1
NKX2-1	NM_003317.4	c.*210delT		3_prime_UTR_variant	Exon 2 of 2		NP_003308.1
SFTA3	NR_161364.1	n.89+2400delT		intron_variant	Intron 1 of 4
SFTA3	NR_161365.1	n.89+2400delT		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKX2-1	ENST00000354822.7	c.*210delT		3_prime_UTR_variant	Exon 3 of 3	1	NM_001079668.3	ENSP00000346879.6
SFTA3	ENST00000546983.2	n.373+1917delT		intron_variant	Intron 2 of 3	4		ENSP00000449302.2

Frequencies

GnomAD3 genomes AF: 0.000429 AC: 62 AN: 144646 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000425

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000438

Gnomad FIN AF: 0.000222

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000138

Gnomad OTH AF: 0.000513

GnomAD4 exome AF: 0.00227 AC: 1645 AN: 725214 Hom.: 1 Cov.: 10 AF XY: 0.00221 AC XY: 798 AN XY: 360436

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00723 AC: 118 AN: 16320

American (AMR) AF: 0.00254 AC: 34 AN: 13400

Ashkenazi Jewish (ASJ) AF: 0.00174 AC: 23 AN: 13214

East Asian (EAS) AF: 0.00119 AC: 32 AN: 26854

South Asian (SAS) AF: 0.00310 AC: 135 AN: 43560

European-Finnish (FIN) AF: 0.00157 AC: 39 AN: 24864

Middle Eastern (MID) AF: 0.00215 AC: 5 AN: 2326

European-Non Finnish (NFE) AF: 0.00215 AC: 1186 AN: 551634

Other (OTH) AF: 0.00221 AC: 73 AN: 33042

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000463 AC: 67 AN: 144762 Hom.: 2 Cov.: 29 AF XY: 0.000569 AC XY: 40 AN XY: 70310

African (AFR) AF: 0.00116 AC: 47 AN: 40384

American (AMR) AF: 0.000424 AC: 6 AN: 14142

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3322

East Asian (EAS) AF: 0.00 AC: 0 AN: 5034

South Asian (SAS) AF: 0.000438 AC: 2 AN: 4562

European-Finnish (FIN) AF: 0.000222 AC: 2 AN: 8994

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.000138 AC: 9 AN: 65218

Other (OTH) AF: 0.000508 AC: 1 AN: 1970

Alfa AF: 0.000124 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.62
Mutation Taster		=100/0	polymorphism

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: rs886050480; hg19: chr14-36986272;