8-98526806-A-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_006281.4(STK3):c.1253T>G(p.Phe418Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000651 in 1,592,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (0 hom.)
• Consequence: STK3 NM_006281.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.66

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.082675755).
• BS2: High AC in GnomAd at 60 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK3	NM_006281.4	c.1253T>G	p.Phe418Cys	missense_variant	10/11	ENST00000419617.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK3	ENST00000419617.7	c.1253T>G	p.Phe418Cys	missense_variant	10/11	1	NM_006281.4	P1

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000345 AC: 84 AN: 243496 Hom.: 0 AF XY: 0.000378 AC XY: 50 AN XY: 132198

Gnomad AFR exome AF: 0.000196

Gnomad AMR exome AF: 0.0000305

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000327

Gnomad NFE exome AF: 0.000655

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000678 AC: 977 AN: 1440190 Hom.: 0 Cov.: 30 AF XY: 0.000658 AC XY: 471 AN XY: 716202

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.0000693

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000266

Gnomad4 NFE exome AF: 0.000851

Gnomad4 OTH exome AF: 0.000406

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152114 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74282

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000779

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000436 Hom.: 0

Bravo AF: 0.000329

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000268 AC: 1

ESP6500EA AF: 0.000365 AC: 3

ExAC AF: 0.000397 AC: 48

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

Oct 06, 2021

The c.1253T>G (p.F418C) alteration is located in exon 10 (coding exon 10) of the STK3 gene. This alteration results from a T to G substitution at nucleotide position 1253, causing the phenylalanine (F) at amino acid position 418 to be replaced by a cysteine (C). 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	0.070
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	20
Dann	Benign	0.93
DEOGEN2	Benign	0.034	T;T;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.73	T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.083	T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	0.98	N;N
PrimateAI	Uncertain	0.56	T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.18	.;B;.
Vest4		0.37
MVP		0.96
MPC		0.15
ClinPred		0.031	T
GERP RS		4.2
Varity_R		0.044
gMVP		0.16

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: rs36047674; hg19: chr8-99539034;