chr14-36517091-A-AGGGTG

Variant names:

• chr14-36517091-A-AGGGTG
• rs141117763
• NM_001079668.3:c.*186_*187insCACCC

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_*187insCACCC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,025,388 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 28)
  • Exomes 𝑓: 0.0019 (6 hom.)
• Consequence: NKX2-1 NM_001079668.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0890
• 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 -10 ACMG points.

• BP6: Variant 14-36517091-A-AGGGTG is Benign according to our data. Variant chr14-36517091-A-AGGGTG is described in ClinVar as [Likely_benign]. Clinvar id is 2644179.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00135 (202/150010) while in subpopulation AMR AF = 0.00398 (60/15072). AF 95% confidence interval is 0.00317. There are 1 homozygotes in GnomAd4. There are 95 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High AC in GnomAd4 at 202 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX2-1	NM_001079668.3	c.*186_*187insCACCC		3_prime_UTR_variant	Exon 3 of 3	ENST00000354822.7	NP_001073136.1
NKX2-1	NM_003317.4	c.*186_*187insCACCC		3_prime_UTR_variant	Exon 2 of 2		NP_003308.1
SFTA3	NR_161364.1	n.89+2376_89+2377insCACCC		intron_variant	Intron 1 of 4
SFTA3	NR_161365.1	n.89+2376_89+2377insCACCC		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_*187insCACCC		3_prime_UTR_variant	Exon 3 of 3	1	NM_001079668.3	ENSP00000346879.6
SFTA3	ENST00000546983.2	n.373+1893_373+1894insCACCC		intron_variant	Intron 2 of 3	4		ENSP00000449302.2

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 202 AN: 149928 Hom.: 1 Cov.: 28

Gnomad AFR AF: 0.000562

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.000578

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000417

Gnomad FIN AF: 0.000103

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00158

Gnomad OTH AF: 0.00340

GnomAD4 exome AF: 0.00186 AC: 1630 AN: 875378 Hom.: 6 Cov.: 12 AF XY: 0.00180 AC XY: 773 AN XY: 430112

African (AFR) AF: 0.000553 AC: 11 AN: 19888

American (AMR) AF: 0.00320 AC: 40 AN: 12508

Ashkenazi Jewish (ASJ) AF: 0.000617 AC: 9 AN: 14594

East Asian (EAS) AF: 0.0000722 AC: 2 AN: 27704

South Asian (SAS) AF: 0.000438 AC: 18 AN: 41128

European-Finnish (FIN) AF: 0.000325 AC: 9 AN: 27712

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2664

European-Non Finnish (NFE) AF: 0.00213 AC: 1469 AN: 690886

Other (OTH) AF: 0.00188 AC: 72 AN: 38294

GnomAD4 genome AF: 0.00135 AC: 202 AN: 150010 Hom.: 1 Cov.: 28 AF XY: 0.00130 AC XY: 95 AN XY: 73068

African (AFR) AF: 0.000560 AC: 23 AN: 41040

American (AMR) AF: 0.00398 AC: 60 AN: 15072

Ashkenazi Jewish (ASJ) AF: 0.000578 AC: 2 AN: 3462

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

South Asian (SAS) AF: 0.000419 AC: 2 AN: 4776

European-Finnish (FIN) AF: 0.000103 AC: 1 AN: 9718

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

European-Non Finnish (NFE) AF: 0.00158 AC: 107 AN: 67548

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

Alfa AF: 0.000167 Hom.: 126

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 01, 2022

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
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: rs141117763; hg19: chr14-36986296;