NM_001079668.3:c.77+328_77+329delCT

Variant names:

• chr14-36519723-AAG-A
• rs149047715
• NM_001079668.3:c.77+328_77+329delCT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001079668.3(NKX2-1):​c.77+328_77+329delCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0235 in 1,263,186 control chromosomes in the GnomAD database, including 30 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0033 (4 hom., cov: 31)
  • Exomes 𝑓: 0.026 (26 hom.)
• Consequence: NKX2-1 NM_001079668.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.31
• Publications: 4 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:):

NKX2-1-AS1 (HGNC:40585): (NKX2-1 antisense RNA 1)

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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00335 (505/150960) while in subpopulation NFE AF = 0.00629 (425/67590). AF 95% confidence interval is 0.00579. There are 4 homozygotes in GnomAd4. There are 207 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 505 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001079668.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKX2-1	NM_001079668.3	MANE Select	c.77+328_77+329delCT		intron	N/A	NP_001073136.1	P43699-3
	NKX2-1-AS1	NR_103710.1		n.402+59_402+60delAG		intron	N/A
	NKX2-1	NM_003317.4		c.-368_-367delCT		upstream_gene	N/A	NP_003308.1	P43699-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKX2-1	ENST00000354822.7	TSL:1 MANE Select	c.77+328_77+329delCT		intron	N/A	ENSP00000346879.6	P43699-3
	NKX2-1	ENST00000522719.4	TSL:1	c.-158-113_-158-112delCT		intron	N/A	ENSP00000429519.4	P43699-1
	SFTA3	ENST00000546983.2	TSL:4	n.-13-355_-13-354delCT		intron	N/A	ENSP00000449302.2	F8VVG2

Frequencies

GnomAD3 genomes AF: 0.00336 AC: 507 AN: 150854 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00119

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00119

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000294

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00629

Gnomad OTH AF: 0.00386

GnomAD4 exome AF: 0.0262 AC: 29182 AN: 1112226 Hom.: 26 AF XY: 0.0275 AC XY: 14959 AN XY: 544648

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

African (AFR) AF: 0.0263 AC: 626 AN: 23786

American (AMR) AF: 0.0430 AC: 1121 AN: 26066

Ashkenazi Jewish (ASJ) AF: 0.0274 AC: 527 AN: 19212

East Asian (EAS) AF: 0.0500 AC: 1164 AN: 23278

South Asian (SAS) AF: 0.0348 AC: 2046 AN: 58716

European-Finnish (FIN) AF: 0.0467 AC: 1157 AN: 24750

Middle Eastern (MID) AF: 0.0135 AC: 65 AN: 4798

European-Non Finnish (NFE) AF: 0.0240 AC: 21237 AN: 886486

Other (OTH) AF: 0.0275 AC: 1239 AN: 45134

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00335 AC: 505 AN: 150960 Hom.: 4 Cov.: 31 AF XY: 0.00281 AC XY: 207 AN XY: 73720

African (AFR) AF: 0.00119 AC: 49 AN: 41330

American (AMR) AF: 0.00119 AC: 18 AN: 15152

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

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

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4796

European-Finnish (FIN) AF: 0.000294 AC: 3 AN: 10202

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00629 AC: 425 AN: 67590

Other (OTH) AF: 0.00382 AC: 8 AN: 2096

Alfa AF: 0.000730 Hom.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
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: rs149047715; hg19: chr14-36988928; COSMIC: COSV61388385; COSMIC: COSV61388385;