14-36516817-CAA-C

Variant names:

• chr14-36516817-CAA-C
• rs5807883
• NM_001079668.3:c.*459_*460delTT

Variant summary

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

The NM_001079668.3(NKX2-1):​c.*459_*460delTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00639 in 216,296 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 0.0025 (3 hom., cov: 0)
  • Exomes 𝑓: 0.014 (0 hom.)
• Consequence: NKX2-1 NM_001079668.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.372
• Publications: 1 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 eas. GnomAd4 allele frequency = 0.00253 (360/142378) while in subpopulation EAS AF = 0.0313 (154/4918). AF 95% confidence interval is 0.0273. There are 3 homozygotes in GnomAd4. There are 175 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 360 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX2-1	NM_001079668.3	c.*459_*460delTT		3_prime_UTR_variant	Exon 3 of 3	ENST00000354822.7	NP_001073136.1
NKX2-1	NM_003317.4	c.*459_*460delTT		3_prime_UTR_variant	Exon 2 of 2		NP_003308.1
SFTA3	NR_161364.1	n.89+2649_89+2650delTT		intron_variant	Intron 1 of 4
SFTA3	NR_161365.1	n.89+2649_89+2650delTT		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKX2-1	ENST00000354822.7	c.*459_*460delTT		3_prime_UTR_variant	Exon 3 of 3	1	NM_001079668.3	ENSP00000346879.6
SFTA3	ENST00000546983.2	n.373+2166_373+2167delTT		intron_variant	Intron 2 of 3	4		ENSP00000449302.2

Frequencies

GnomAD3 genomes AF: 0.00253 AC: 360 AN: 142320 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.00390

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0312

Gnomad SAS AF: 0.00362

Gnomad FIN AF: 0.000682

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000214

Gnomad OTH AF: 0.00203

GnomAD4 exome AF: 0.0138 AC: 1023 AN: 73918 Hom.: 0 AF XY: 0.0134 AC XY: 458 AN XY: 34066

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

African (AFR) AF: 0.00794 AC: 28 AN: 3526

American (AMR) AF: 0.0230 AC: 51 AN: 2222

Ashkenazi Jewish (ASJ) AF: 0.00444 AC: 21 AN: 4734

East Asian (EAS) AF: 0.0509 AC: 510 AN: 10014

South Asian (SAS) AF: 0.0102 AC: 7 AN: 688

European-Finnish (FIN) AF: 0.0349 AC: 3 AN: 86

Middle Eastern (MID) AF: 0.00881 AC: 4 AN: 454

European-Non Finnish (NFE) AF: 0.00724 AC: 333 AN: 45984

Other (OTH) AF: 0.0106 AC: 66 AN: 6210

⚠️ 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: 0.00253 AC: 360 AN: 142378 Hom.: 3 Cov.: 0 AF XY: 0.00254 AC XY: 175 AN XY: 68882

African (AFR) AF: 0.00390 AC: 147 AN: 37736

American (AMR) AF: 0.00131 AC: 19 AN: 14510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3344

East Asian (EAS) AF: 0.0313 AC: 154 AN: 4918

South Asian (SAS) AF: 0.00363 AC: 16 AN: 4406

European-Finnish (FIN) AF: 0.000682 AC: 6 AN: 8798

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 270

European-Non Finnish (NFE) AF: 0.000214 AC: 14 AN: 65526

Other (OTH) AF: 0.00201 AC: 4 AN: 1988

Alfa AF: 0.00 Hom.: 504

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.37
Mutation Taster		=99/1	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: rs5807883; hg19: chr14-36986022; COSMIC: COSV61390673; COSMIC: COSV61390673;