4-1406384-T-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001290079.1(NKX1-1):​c.59A>C​(p.Gln20Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000976 in 204,974 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000098 (0 hom.)
• Consequence: NKX1-1 NM_001290079.1 missense
• Clinical Significance: Not reported in ClinVar
• 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: 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=-0.85).

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>C	p.Gln20Pro	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>C	p.Gln20Pro	missense	Exon 1 of 2	ENSP00000407978.2	Q15270

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000976 AC: 2 AN: 204974 Hom.: 0 AF XY: 0.0000190 AC XY: 2 AN XY: 105158

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

African (AFR) AF: 0.00 AC: 0 AN: 5346

American (AMR) AF: 0.00 AC: 0 AN: 5942

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6988

East Asian (EAS) AF: 0.0000536 AC: 1 AN: 18656

South Asian (SAS) AF: 0.00 AC: 0 AN: 2762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1032

European-Non Finnish (NFE) AF: 0.00000760 AC: 1 AN: 131630

Other (OTH) AF: 0.00 AC: 0 AN: 13010

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000812204), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 1719

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.6
DANN	Benign	0.088
PhyloP100		-0.29
PromoterAI		0.016	Neutral

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;