8-98455849-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006281.4(STK3):c.1469A>G(p.Asn490Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: STK3 NM_006281.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.63

Genes affected

STK3 (HGNC:11406): (serine/threonine kinase 3) This gene encodes a serine/threonine protein kinase activated by proapoptotic molecules indicating the encoded protein functions as a growth suppressor. Cleavage of the protein product by caspase removes the inhibitory C-terminal portion. The N-terminal portion is transported to the nucleus where it homodimerizes to form the active kinase which promotes the condensation of chromatin during apoptosis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK3	NM_006281.4	c.1469A>G	p.Asn490Ser	missense_variant	11/11	ENST00000419617.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK3	ENST00000419617.7	c.1469A>G	p.Asn490Ser	missense_variant	11/11	1	NM_006281.4	P1
STK3	ENST00000523601.5	c.1553A>G	p.Asn518Ser	missense_variant	13/13	2
STK3	ENST00000617590.1	c.1136A>G	p.Asn379Ser	missense_variant	9/9	5
STK3	ENST00000517832.1	n.186-18641A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Sep 23, 2023

The c.1469A>G (p.N490S) alteration is located in exon 11 (coding exon 11) of the STK3 gene. This alteration results from a A to G substitution at nucleotide position 1469, causing the asparagine (N) at amino acid position 490 to be replaced by a serine (S). 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	0.28
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.24	T;T;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.086	D
MetaRNN	Uncertain	0.65	D;D;D
MetaSVM	Uncertain	0.21	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.82	D
Sift4G	Uncertain	0.011	D;D;D
Polyphen		0.98	.;D;.
Vest4		0.61
MutPred		0.22		.;Gain of phosphorylation at N490 (P = 0.0056);.;
MVP		0.95
MPC		0.33
ClinPred		0.96	D
GERP RS		5.1
Varity_R		0.39
gMVP		0.47

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: chr8-99468077;