20-2102054-C-A

Position:

• chr20-2102054-C-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_080836.4(STK35):​c.173C>A​(p.Ala58Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000365 in 1,371,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.0000036 (0 hom.)
• Consequence: STK35 NM_080836.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.335

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08232039).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK35	NM_080836.4	c.173C>A	p.Ala58Asp	missense_variant	1/4	ENST00000381482.8	NP_543026.2
STK35	XM_011529174.4	c.173C>A	p.Ala58Asp	missense_variant	1/3		XP_011527476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK35	ENST00000381482.8	c.173C>A	p.Ala58Asp	missense_variant	1/4	5	NM_080836.4	ENSP00000370891	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000365 AC: 5 AN: 1371408 Hom.: 0 Cov.: 30 AF XY: 0.00000592 AC XY: 4 AN XY: 675464

Gnomad4 AFR exome AF: 0.0000329

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: 0.00000373

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 04, 2024

The c.173C>A (p.A58D) alteration is located in exon 1 (coding exon 1) of the STK35 gene. This alteration results from a C to A substitution at nucleotide position 173, causing the alanine (A) at amino acid position 58 to be replaced by an aspartic acid (D). 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	0.11
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	14
DANN	Benign	0.88
DEOGEN2	Benign	0.0040	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.22	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.046
Sift	Uncertain	0.010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.012	B
Vest4		0.15
MutPred		0.30		Loss of helix (P = 0.0068);
MVP		0.22
MPC		1.5
ClinPred		0.14	T
GERP RS		0.94
Varity_R		0.20
gMVP		0.45

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: rs1169017337; hg19: chr20-2082700;