NM_001189.4:c.873A>C

Variant names:

• chr4-13542122-T-G
• NM_001189.4:c.873A>C

Variant summary

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

The NM_001189.4(NKX3-2):​c.873A>C​(p.Arg291Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,110 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NKX3-2 NM_001189.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.54

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, 0.781

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX3-2	NM_001189.4	c.873A>C	p.Arg291Ser	missense_variant	Exon 2 of 2	ENST00000382438.6	NP_001180.1
NKX3-2	XM_047416049.1	c.873A>C	p.Arg291Ser	missense_variant	Exon 3 of 3		XP_047272005.1
NKX3-2	XM_047416050.1	c.873A>C	p.Arg291Ser	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.873A>C	p.Arg291Ser	missense_variant	Exon 2 of 2	1	NM_001189.4	ENSP00000371875.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459110 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725492

Gnomad4 AFR exome AF: 0.0000299

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.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Uncertain	2.1	M
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.032	D
Polyphen		0.98	D
Vest4		0.56
MutPred		0.41		Loss of sheet (P = 0.0181);
MVP		0.90
MPC		1.1
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.52
gMVP		0.77

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: chr4-13543746;