4-1406384-T-C

Variant names:

• chr4-1406384-T-C
• rs72613115
• NM_001290079.1:c.59A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 5/5 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.288
• Publications: 9 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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>G	p.Gln20Arg	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>G	p.Gln20Arg	missense	Exon 1 of 2	ENSP00000407978.2	Q15270

Frequencies

GnomAD3 genomes AF: 0.709 AC: 106459 AN: 150256 Hom.: 37884 Cov.: 32

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

African (AFR) AF: 0.748 AC: 3984 AN: 5324

American (AMR) AF: 0.803 AC: 4766 AN: 5938

Ashkenazi Jewish (ASJ) AF: 0.588 AC: 4097 AN: 6964

East Asian (EAS) AF: 0.685 AC: 12749 AN: 18600

South Asian (SAS) AF: 0.656 AC: 1808 AN: 2756

European-Finnish (FIN) AF: 0.702 AC: 13745 AN: 19568

Middle Eastern (MID) AF: 0.600 AC: 616 AN: 1026

European-Non Finnish (NFE) AF: 0.661 AC: 86759 AN: 131348

Other (OTH) AF: 0.670 AC: 8691 AN: 12976

GnomAD4 genome AF: 0.709 AC: 106549 AN: 150364 Hom.: 37921 Cov.: 32 AF XY: 0.709 AC XY: 52065 AN XY: 73384

African (AFR) AF: 0.758 AC: 31267 AN: 41266

American (AMR) AF: 0.761 AC: 11526 AN: 15140

Ashkenazi Jewish (ASJ) AF: 0.610 AC: 2091 AN: 3426

East Asian (EAS) AF: 0.713 AC: 3599 AN: 5048

South Asian (SAS) AF: 0.680 AC: 3280 AN: 4820

European-Finnish (FIN) AF: 0.717 AC: 7228 AN: 10074

Middle Eastern (MID) AF: 0.600 AC: 174 AN: 290

European-Non Finnish (NFE) AF: 0.674 AC: 45337 AN: 67314

Other (OTH) AF: 0.654 AC: 1362 AN: 2084

Alfa AF: 0.603 Hom.: 1719

Bravo AF: 0.715

Asia WGS AF: 0.670 AC: 2082 AN: 3104

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_noAF	Benign	-0.91
CADD	Benign	5.3
DANN	Benign	0.063
PhyloP100		-0.29
PromoterAI		0.0068	Neutral
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: rs72613115; hg19: chr4-1400172; COSMIC: COSV107522217;