11-8413553-T-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001352389.2(STK33):c.1286A>C(p.Gln429Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000598 in 1,614,088 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (1 hom.)
• Consequence: STK33 NM_001352389.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.101

Genes affected

STK33 (HGNC:14568): (serine/threonine kinase 33) Predicted to enable protein serine/threonine kinase activity. Predicted to be involved in mitotic DNA damage checkpoint signaling and protein autophosphorylation. Predicted to be located in perinuclear region of cytoplasm. Predicted to be active in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.022287756).
• BP6: Variant 11-8413553-T-G is Benign according to our data. Variant chr11-8413553-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2641580.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK33	NM_001352389.2	c.1286A>C	p.Gln429Pro	missense_variant	15/16	ENST00000687296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK33	ENST00000687296.1	c.1286A>C	p.Gln429Pro	missense_variant	15/16		NM_001352389.2	P1

Frequencies

GnomAD3 genomes AF: 0.000421 AC: 64 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000853

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000422 AC: 106 AN: 251450 Hom.: 0 AF XY: 0.000412 AC XY: 56 AN XY: 135902

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000853

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000616 AC: 901 AN: 1461782 Hom.: 1 Cov.: 32 AF XY: 0.000582 AC XY: 423 AN XY: 727192

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000779

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.000420 AC: 64 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74484

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000853

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000725 Hom.: 0

Bravo AF: 0.000419

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000486 AC: 59

EpiCase AF: 0.000491

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 10, 2022

The c.1286A>C (p.Q429P) alteration is located in exon 13 (coding exon 11) of the STK33 gene. This alteration results from a A to C substitution at nucleotide position 1286, causing the glutamine (Q) at amino acid position 429 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2022

STK33: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	6.0
Dann	Benign	0.66
DEOGEN2	Benign	0.0041	T;T;T;T;T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.016	N
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.022	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.69	N;N;N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.020	N;N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.23	T;T;T;T;T
Sift4G	Benign	0.28	T;T;T;T;T
Polyphen		0.0	B;B;B;.;.
Vest4		0.16
MVP		0.67
MPC		0.092
ClinPred		0.0064	T
GERP RS		2.6
Varity_R		0.13
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: rs140349792; hg19: chr11-8435100;