10-99533438-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_145285.3(NKX2-3):c.307G>A(p.Glu103Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000624 in 1,441,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: NKX2-3 NM_145285.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.69

Genes affected

NKX2-3 (HGNC:7836): (NK2 homeobox 3) This gene encodes a homeodomain-containing transcription factor. The encoded protein is a member of the NKX family of homeodomain transcription factors. Studies of similar proteins in mouse and rat have indicated a potential role in cellular differentiation.[provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07254946).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NKX2-3	NM_145285.3	c.307G>A	p.Glu103Lys	missense_variant	1/2	ENST00000344586.9
NKX2-3	XM_011539370.2	c.307G>A	p.Glu103Lys	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NKX2-3	ENST00000344586.9	c.307G>A	p.Glu103Lys	missense_variant	1/2	2	NM_145285.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000624 AC: 9 AN: 1441998 Hom.: 0 Cov.: 34 AF XY: 0.0000126 AC XY: 9 AN XY: 714998

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000249

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000241

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000453

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 11, 2022

The c.307G>A (p.E103K) alteration is located in exon 1 (coding exon 1) of the NKX2-3 gene. This alteration results from a G to A substitution at nucleotide position 307, causing the glutamic acid (E) at amino acid position 103 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	17
Dann	Benign	0.77
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.41	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.073	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.54	N;.
REVEL	Benign	0.15
Sift	Benign	0.71	T;.
Sift4G	Benign	0.64	T;T
Polyphen		0.0030	B;.
Vest4		0.094
MutPred		0.43		Gain of ubiquitination at E103 (P = 0.0022);Gain of ubiquitination at E103 (P = 0.0022);
MVP		0.28
ClinPred		0.036	T
GERP RS		4.0
Varity_R		0.069
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-101293195; COSMIC: COSV60728929; COSMIC: COSV60728929;