14-36517091-A-AGGGTGGG

Variant names:

• chr14-36517091-A-AGGGTGGG
• rs141117763
• NM_001079668.3:c.*186_*187insCCCACCC

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS1

The NM_001079668.3(NKX2-1):​c.*186_*187insCCCACCC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0014 (4 hom.)
  • Failed GnomAD Quality Control
• 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 14-36517091-A-AGGGTGGG is Benign according to our data. Variant chr14-36517091-A-AGGGTGGG is described in ClinVar as [Likely_benign]. Clinvar id is 2570877.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00142 (1241/876360) while in subpopulation NFE AF = 0.0016 (1104/691648). AF 95% confidence interval is 0.00152. There are 4 homozygotes in GnomAdExome4. There are 632 alleles in the male GnomAdExome4 subpopulation. Median coverage is 12. This position passed quality control check.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 215 AN: 149882 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000318

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00159

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000389

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000823

Gnomad MID AF: 0.00645

Gnomad NFE AF: 0.00235

Gnomad OTH AF: 0.000972

GnomAD4 exome AF: 0.00142 AC: 1241 AN: 876360 Hom.: 4 Cov.: 12 AF XY: 0.00147 AC XY: 632 AN XY: 430598

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

African (AFR) AF: 0.000452 AC: 9 AN: 19890

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

Ashkenazi Jewish (ASJ) AF: 0.00150 AC: 22 AN: 14650

East Asian (EAS) AF: 0.000650 AC: 18 AN: 27710

South Asian (SAS) AF: 0.000413 AC: 17 AN: 41150

European-Finnish (FIN) AF: 0.000757 AC: 21 AN: 27742

Middle Eastern (MID) AF: 0.000750 AC: 2 AN: 2666

European-Non Finnish (NFE) AF: 0.00160 AC: 1104 AN: 691648

Other (OTH) AF: 0.000990 AC: 38 AN: 38372

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.00143 AC: 214 AN: 149964 Hom.: 0 Cov.: 28 AF XY: 0.00126 AC XY: 92 AN XY: 73042

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

African (AFR) AF: 0.000317 AC: 13 AN: 41034

American (AMR) AF: 0.00153 AC: 23 AN: 15068

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3462

East Asian (EAS) AF: 0.000390 AC: 2 AN: 5124

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

European-Finnish (FIN) AF: 0.000823 AC: 8 AN: 9718

Middle Eastern (MID) AF: 0.00694 AC: 2 AN: 288

European-Non Finnish (NFE) AF: 0.00236 AC: 159 AN: 67512

Other (OTH) AF: 0.000962 AC: 2 AN: 2078

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

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

Apr 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: rs141117763; hg19: chr14-36986296;