14-36517091-AG-AGG

Variant names:

• chr14-36517091-A-AG
• rs1555349072
• NM_001079668.3:c.*186dupC

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.*186dupC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 1,026,606 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00015 (2 hom.)
• Consequence: NKX2-1 NM_001079668.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.0890
• 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: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00016 (24/149928) while in subpopulation AFR AF = 0.0000733 (3/40934). AF 95% confidence interval is 0.0000198. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 28. 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 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX2-1	NM_001079668.3	c.*186dupC		3_prime_UTR_variant	Exon 3 of 3	ENST00000354822.7	NP_001073136.1
NKX2-1	NM_003317.4	c.*186dupC		3_prime_UTR_variant	Exon 2 of 2		NP_003308.1
SFTA3	NR_161364.1	n.89+2376dupC		intron_variant	Intron 1 of 4
SFTA3	NR_161365.1	n.89+2376dupC		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKX2-1	ENST00000354822.7	c.*186dupC		3_prime_UTR_variant	Exon 3 of 3	1	NM_001079668.3	ENSP00000346879.6
SFTA3	ENST00000546983.2	n.373+1893dupC		intron_variant	Intron 2 of 3	4		ENSP00000449302.2

Frequencies

GnomAD3 genomes AF: 0.000160 AC: 24 AN: 149928 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000733

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000592

Gnomad OTH AF: 0.000972

GnomAD4 exome AF: 0.000146 AC: 128 AN: 876678 Hom.: 2 Cov.: 12 AF XY: 0.000144 AC XY: 62 AN XY: 430758

African (AFR) AF: 0.0000503 AC: 1 AN: 19888

American (AMR) AF: 0.00 AC: 0 AN: 12532

Ashkenazi Jewish (ASJ) AF: 0.00593 AC: 87 AN: 14660

East Asian (EAS) AF: 0.00 AC: 0 AN: 27734

South Asian (SAS) AF: 0.0000972 AC: 4 AN: 41148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27748

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2668

European-Non Finnish (NFE) AF: 0.0000405 AC: 28 AN: 691920

Other (OTH) AF: 0.000208 AC: 8 AN: 38380

GnomAD4 genome AF: 0.000160 AC: 24 AN: 149928 Hom.: 0 Cov.: 28 AF XY: 0.000233 AC XY: 17 AN XY: 72974

African (AFR) AF: 0.0000733 AC: 3 AN: 40934

American (AMR) AF: 0.00 AC: 0 AN: 15054

Ashkenazi Jewish (ASJ) AF: 0.00433 AC: 15 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9718

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000592 AC: 4 AN: 67558

Other (OTH) AF: 0.000972 AC: 2 AN: 2058

Alfa AF: 0.00 Hom.: 0

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		0.089

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: rs1555349072; hg19: chr14-36986296;