chr14-36516817-C-CAA

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001079668.3(NKX2-1):​c.*459_*460dupTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0047 (3 hom., cov: 0)
  • Exomes 𝑓: 0.018 (0 hom.)
• Consequence: NKX2-1 NM_001079668.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -1.44
• 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: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00468 (666/142392) while in subpopulation SAS AF = 0.0132 (58/4406). AF 95% confidence interval is 0.0105. There are 3 homozygotes in GnomAd4. There are 346 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 666 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX2-1	NM_001079668.3	c.*459_*460dupTT		3_prime_UTR_variant	Exon 3 of 3	ENST00000354822.7	NP_001073136.1
NKX2-1	NM_003317.4	c.*459_*460dupTT		3_prime_UTR_variant	Exon 2 of 2		NP_003308.1
SFTA3	NR_161364.1	n.89+2649_89+2650dupTT		intron_variant	Intron 1 of 4
SFTA3	NR_161365.1	n.89+2649_89+2650dupTT		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_*460dupTT		3_prime_UTR_variant	Exon 3 of 3	1	NM_001079668.3	ENSP00000346879.6
SFTA3	ENST00000546983.2	n.373+2166_373+2167dupTT		intron_variant	Intron 2 of 3	4		ENSP00000449302.2

Frequencies

GnomAD3 genomes AF: 0.00465 AC: 662 AN: 142334 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.00460

Gnomad AMI AF: 0.0249

Gnomad AMR AF: 0.00442

Gnomad ASJ AF: 0.000598

Gnomad EAS AF: 0.00547

Gnomad SAS AF: 0.0131

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00436

Gnomad OTH AF: 0.00761

GnomAD4 exome AF: 0.0181 AC: 1346 AN: 74446 Hom.: 0 Cov.: 0 AF XY: 0.0183 AC XY: 626 AN XY: 34288

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

African (AFR) AF: 0.0132 AC: 47 AN: 3566

American (AMR) AF: 0.0147 AC: 33 AN: 2250

Ashkenazi Jewish (ASJ) AF: 0.0129 AC: 61 AN: 4722

East Asian (EAS) AF: 0.0227 AC: 234 AN: 10308

South Asian (SAS) AF: 0.0174 AC: 12 AN: 688

European-Finnish (FIN) AF: 0.0116 AC: 1 AN: 86

Middle Eastern (MID) AF: 0.00219 AC: 1 AN: 456

European-Non Finnish (NFE) AF: 0.0178 AC: 823 AN: 46146

Other (OTH) AF: 0.0215 AC: 134 AN: 6224

⚠️ 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: 0.00468 AC: 666 AN: 142392 Hom.: 3 Cov.: 0 AF XY: 0.00502 AC XY: 346 AN XY: 68882

African (AFR) AF: 0.00466 AC: 176 AN: 37732

American (AMR) AF: 0.00441 AC: 64 AN: 14510

Ashkenazi Jewish (ASJ) AF: 0.000598 AC: 2 AN: 3342

East Asian (EAS) AF: 0.00549 AC: 27 AN: 4918

South Asian (SAS) AF: 0.0132 AC: 58 AN: 4406

European-Finnish (FIN) AF: 0.00170 AC: 15 AN: 8806

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

European-Non Finnish (NFE) AF: 0.00436 AC: 286 AN: 65536

Other (OTH) AF: 0.00804 AC: 16 AN: 1990

Alfa AF: 0.00185 Hom.: 504

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Brain-lung-thyroid syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Benign hereditary chorea Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs5807883; hg19: chr14-36986022;