Genetic Variant NKX2-1:c.77+326_77+329delCTCT (chr14-36519723-AAGAG-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_001079668.3(NKX2-1):c.77+326_77+329delCTCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000169 in 1,447,520 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

NKX2-1
NM_001079668.3 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.31

Publications

4 publications found

Variant links:

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]

NKX2-1 links:

SFTA3 (HGNC:):

SFTA3 links:

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

NKX2-1-AS1 links:

SFTA3 (HGNC:18387): (surfactant associated 3) Involved in wound healing. Located in cytoplasm and extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

SFTA3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000112 (17/151186) while in subpopulation SAS AF = 0.000625 (3/4800). AF 95% confidence interval is 0.000169. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 17 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NKX2-1	NM_001079668.3	MANE Select	c.77+326_77+329delCTCT	intron	N/A	NP_001073136.1	P43699-3
NKX2-1-AS1	NR_103710.1		n.402+57_402+60delAGAG	intron	N/A
NKX2-1	NM_003317.4		c.-370_-367delCTCT	upstream_gene	N/A	NP_003308.1	P43699-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NKX2-1	ENST00000354822.7	TSL:1 MANE Select	c.77+326_77+329delCTCT	intron	N/A	ENSP00000346879.6	P43699-3
NKX2-1	ENST00000522719.4	TSL:1	c.-158-115_-158-112delCTCT	intron	N/A	ENSP00000429519.4	P43699-1
SFTA3	ENST00000546983.2	TSL:4	n.-13-357_-13-354delCTCT	intron	N/A	ENSP00000449302.2	F8VVG2

Frequencies

GnomAD3 genomes

AF:

0.000106

AC:

AN:

151078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000218

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000624

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.0000296

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000175

AC:

227

AN:

1296334

Hom.:

AF XY:

0.000192

AC XY:

122

AN XY:

635682

show subpopulations

African (AFR)

AF:

0.000578

AC:

AN:

29432

American (AMR)

AF:

0.000188

AC:

AN:

31992

Ashkenazi Jewish (ASJ)

AF:

0.0000442

AC:

AN:

22606

East Asian (EAS)

AF:

0.000127

AC:

AN:

31526

South Asian (SAS)

AF:

0.000854

AC:

AN:

72562

European-Finnish (FIN)

AF:

0.000102

AC:

AN:

29376

Middle Eastern (MID)

AF:

0.000755

AC:

AN:

5296

European-Non Finnish (NFE)

AF:

0.000109

AC:

111

AN:

1019894

Other (OTH)

AF:

0.000354

AC:

AN:

53650

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.421

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000112

AC:

AN:

151186

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

73842

show subpopulations

African (AFR)

AF:

0.000242

AC:

AN:

41358

American (AMR)

AF:

0.00

AC:

AN:

15180

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5140

South Asian (SAS)

AF:

0.000625

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10284

Middle Eastern (MID)

AF:

0.00690

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000296

AC:

AN:

67666

Other (OTH)

AF:

0.00

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000110

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.3

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over