20-2102952-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_080836.4(STK35):c.479C>T(p.Pro160Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000075 in 1,333,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: STK35 NM_080836.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.187

Genes affected

STK35 (HGNC:16254): (serine/threonine kinase 35) The protein encoded by this gene is a kinase that is predominantly found in the nucleus. However, it can interact with PDLIM1/CLP-36 in the cytoplasm and localize to actin stress fibers. The encoded protein may be a regulator of actin stress fibers in nonmuscle cells. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09354904).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK35	NM_080836.4	c.479C>T	p.Pro160Leu	missense_variant	2/4	ENST00000381482.8
STK35	XM_011529174.4	c.479C>T	p.Pro160Leu	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK35	ENST00000381482.8	c.479C>T	p.Pro160Leu	missense_variant	2/4	5	NM_080836.4	P1
STK35	ENST00000493263.1	c.62C>T	p.Pro21Leu	missense_variant, NMD_transcript_variant	1/4	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.50e-7 AC: 1 AN: 1333918 Hom.: 0 Cov.: 31 AF XY: 0.00000152 AC XY: 1 AN XY: 658686

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000337

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

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

Apr 07, 2023

The c.479C>T (p.P160L) alteration is located in exon 2 (coding exon 2) of the STK35 gene. This alteration results from a C to T substitution at nucleotide position 479, causing the proline (P) at amino acid position 160 to be replaced by a leucine (L). 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	0.069
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0028	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.0094	N
LIST_S2	Benign	0.64	T
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N
MutationTaster	Benign	0.66	D;D;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.15
Sift	Benign	0.23	T
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.22		Loss of glycosylation at P160 (P = 0.0207);
MVP		0.20
MPC		1.1
ClinPred		0.14	T
GERP RS		1.6
Varity_R		0.040
gMVP		0.32

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: rs1985432085; hg19: chr20-2083598;