14-36517091-A-AGAGTGG

Variant names:

• chr14-36517091-A-AGAGTGG
• rs1555349073
• NM_001079668.3:c.*186_*187insCCACTC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001079668.3(NKX2-1):​c.*186_*187insCCACTC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 1,026,700 control chromosomes in the GnomAD database, including 24 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0027 (24 hom.)
• Consequence: NKX2-1 NM_001079668.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0890

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 -10 ACMG points.

• BP6: Variant 14-36517091-A-AGAGTGG is Benign according to our data. Variant chr14-36517091-A-AGAGTGG is described in ClinVar as [Likely_benign]. Clinvar id is 2644178.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00214 (321/150004) while in subpopulation NFE AF = 0.0037 (250/67546). AF 95% confidence interval is 0.00332. There are 0 homozygotes in GnomAd4. There are 158 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High AC in GnomAd4 at 321 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX2-1	NM_001079668.3	c.*186_*187insCCACTC		3_prime_UTR_variant	Exon 3 of 3	ENST00000354822.7	NP_001073136.1
NKX2-1	NM_003317.4	c.*186_*187insCCACTC		3_prime_UTR_variant	Exon 2 of 2		NP_003308.1
SFTA3	NR_161364.1	n.89+2376_89+2377insCCACTC		intron_variant	Intron 1 of 4
SFTA3	NR_161365.1	n.89+2376_89+2377insCCACTC		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKX2-1	ENST00000354822.7	c.*186_*187insCCACTC		3_prime_UTR_variant	Exon 3 of 3	1	NM_001079668.3	ENSP00000346879.6
SFTA3	ENST00000546983.2	n.373+1893_373+1894insCCACTC		intron_variant	Intron 2 of 3	4		ENSP00000449302.2

Frequencies

GnomAD3 genomes AF: 0.00214 AC: 321 AN: 149922 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000879

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000930

Gnomad ASJ AF: 0.00116

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00103

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00370

Gnomad OTH AF: 0.00340

GnomAD4 exome AF: 0.00271 AC: 2374 AN: 876696 Hom.: 24 Cov.: 12 AF XY: 0.00263 AC XY: 1133 AN XY: 430774

African (AFR) AF: 0.000402 AC: 8 AN: 19890

American (AMR) AF: 0.000798 AC: 10 AN: 12532

Ashkenazi Jewish (ASJ) AF: 0.00157 AC: 23 AN: 14660

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 41152

European-Finnish (FIN) AF: 0.00371 AC: 103 AN: 27752

Middle Eastern (MID) AF: 0.000375 AC: 1 AN: 2668

European-Non Finnish (NFE) AF: 0.00310 AC: 2144 AN: 691926

Other (OTH) AF: 0.00221 AC: 85 AN: 38382

GnomAD4 genome AF: 0.00214 AC: 321 AN: 150004 Hom.: 0 Cov.: 28 AF XY: 0.00216 AC XY: 158 AN XY: 73066

African (AFR) AF: 0.000877 AC: 36 AN: 41040

American (AMR) AF: 0.000929 AC: 14 AN: 15072

Ashkenazi Jewish (ASJ) AF: 0.00116 AC: 4 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.00 AC: 0 AN: 4776

European-Finnish (FIN) AF: 0.00103 AC: 10 AN: 9714

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00370 AC: 250 AN: 67546

Other (OTH) AF: 0.00337 AC: 7 AN: 2078

Alfa AF: 0.00170 Hom.: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NKX2-1: BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.089

Splicing

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

Publications

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Other links and lift over

dbSNP: rs1555349073; hg19: chr14-36986296;