Genetic Variant NKX1-1:p.Gln20Arg (chr4-1406384-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001290079.1(NKX1-1):c.59A>G(p.Gln20Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.687 in 354,864 control chromosomes in the GnomAD database, including 84,135 homozygotes. In-silico tool predicts a benign outcome for this variant. 4/4 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.71 ( 37921 hom., cov: 32)

Exomes 𝑓: 0.67 ( 46214 hom. )

Consequence

NKX1-1
NM_001290079.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.288

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 made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 4-1406384-T-C is Benign according to our data. Variant chr4-1406384-T-C is described in ClinVar as [Benign]. Clinvar id is 769284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.751 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX1-1	NM_001290079.1 link	c.59A>G	p.Gln20Arg	missense_variant	Exon 1 of 2	ENST00000422806.2	NP_001277008.1	Q15270

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKX1-1	ENST00000422806.2 link	c.59A>G	p.Gln20Arg	missense_variant	Exon 1 of 2	5	NM_001290079.1	ENSP00000407978.2		Q15270

Frequencies

GnomAD3 genomes

AF:

0.709

AC:

106459

AN:

150256

Hom.:

37884

Cov.:

show subpopulations

Gnomad AFR

AF:

0.757

Gnomad AMI

AF:

0.759

Gnomad AMR

AF:

0.761

Gnomad ASJ

AF:

0.610

Gnomad EAS

AF:

0.713

Gnomad SAS

AF:

0.682

Gnomad FIN

AF:

0.717

Gnomad MID

AF:

0.600

Gnomad NFE

AF:

0.674

Gnomad OTH

AF:

0.655

GnomAD4 exome

AF:

0.671

AC:

137215

AN:

204500

Hom.:

46214

AF XY:

0.670

AC XY:

70293

AN XY:

104920

show subpopulations

Gnomad4 AFR exome

AF:

0.748

Gnomad4 AMR exome

AF:

0.803

Gnomad4 ASJ exome

AF:

0.588

Gnomad4 EAS exome

AF:

0.685

Gnomad4 SAS exome

AF:

0.656

Gnomad4 FIN exome

AF:

0.702

Gnomad4 NFE exome

AF:

0.661

Gnomad4 OTH exome

AF:

0.670

GnomAD4 genome

AF:

0.709

AC:

106549

AN:

150364

Hom.:

37921

Cov.:

AF XY:

0.709

AC XY:

52065

AN XY:

73384

show subpopulations

Gnomad4 AFR

AF:

0.758

Gnomad4 AMR

AF:

0.761

Gnomad4 ASJ

AF:

0.610

Gnomad4 EAS

AF:

0.713

Gnomad4 SAS

AF:

0.680

Gnomad4 FIN

AF:

0.717

Gnomad4 NFE

AF:

0.674

Gnomad4 OTH

AF:

0.654

Alfa

AF:

0.603

Hom.:

1719

Bravo

AF:

0.715

Asia WGS

AF:

0.670

AC:

2082

AN:

3104

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 17, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

5.3

DANN

Benign

0.063

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over