chr4-13542097-G-A

Variant names:

• chr4-13542097-G-A
• rs1401748209
• NM_001189.4:c.898C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001189.4(NKX3-2):​c.898C>T​(p.Arg300Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NKX3-2 NM_001189.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.43

Genes affected

NKX3-2 (HGNC:951): (NK3 homeobox 2) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in cell differentiation; negative regulation of chondrocyte differentiation; and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including animal organ development; embryonic skeletal system development; and intestinal epithelial cell development. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.815

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX3-2	NM_001189.4	c.898C>T	p.Arg300Trp	missense_variant	Exon 2 of 2	ENST00000382438.6	NP_001180.1
NKX3-2	XM_047416049.1	c.898C>T	p.Arg300Trp	missense_variant	Exon 3 of 3		XP_047272005.1
NKX3-2	XM_047416050.1	c.898C>T	p.Arg300Trp	missense_variant	Exon 3 of 3		XP_047272006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKX3-2	ENST00000382438.6	c.898C>T	p.Arg300Trp	missense_variant	Exon 2 of 2	1	NM_001189.4	ENSP00000371875.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1454240 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 722064

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Benign	2.0	M
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.52
MutPred		0.53		Loss of disorder (P = 0.0192);
MVP		0.97
MPC		1.1
ClinPred		1.0	D
GERP RS		1.9
Varity_R		0.38
gMVP		0.78

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

LitVar

Other links and lift over

dbSNP: rs1401748209; hg19: chr4-13543721;