Genetic Variant NM_001290079.1:c.59A>T (chr4-1406384-T-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001290079.1(NKX1-1):c.59A>T(p.Gln20Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000665 in 150,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 5/5 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q20R) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NKX1-1
NM_001290079.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.288

Publications

9 publications found

Variant links:

Genes affected

NKX1-1 (HGNC:24975): (NK1 homeobox 1) This gene encodes a transcription factor that belongs to NKX family of homeodomain-containing proteins which are critical regulators of organ development. In mice, the orthologous gene is expressed predominantly in the brainstem, in the vicinity of serotonergic neurons, and is required for the coordinated crosstalk of factors involved in the maintenance of energy homeostasis. Mice with a knockout of the orthologous gene lack subcutaneous fat and intra-abdominal epididymal and mesenteric white adipose tissue two weeks after birth, and die within three weeks after birth. [provided by RefSeq, Jul 2017]

NKX1-1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001290079.1. 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
	NKX1-1	NM_001290079.1	MANE Select	c.59A>T	p.Gln20Leu	missense	Exon 1 of 2	NP_001277008.1	Q15270

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKX1-1	ENST00000422806.2	TSL:5 MANE Select	c.59A>T	p.Gln20Leu	missense	Exon 1 of 2	ENSP00000407978.2	Q15270

Frequencies

GnomAD3 genomes

AF:

0.00000665

AC:

AN:

150300

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

204974

Hom.:

AF XY:

0.00

AC XY:

AN XY:

105158

African (AFR)

AF:

0.00

AC:

AN:

5346

American (AMR)

AF:

0.00

AC:

AN:

5942

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

6988

East Asian (EAS)

AF:

0.00

AC:

AN:

18656

South Asian (SAS)

AF:

0.00

AC:

AN:

2762

European-Finnish (FIN)

AF:

0.00

AC:

AN:

19608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1032

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

131630

Other (OTH)

AF:

0.00

AC:

AN:

13010

GnomAD4 genome

AF:

0.00000665

AC:

AN:

150300

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73292

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41160

American (AMR)

AF:

0.00

AC:

AN:

15124

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3428

East Asian (EAS)

AF:

0.00

AC:

AN:

5068

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10082

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67340

Other (OTH)

AF:

0.00

AC:

AN:

2062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

1719

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_noAF

Benign

-0.84

CADD

Benign

6.4

(source)

DANN

Benign

0.18

PhyloP100

-0.29

PromoterAI

-0.012

Neutral

(source)

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over