12-10629593-A-G

Position:

• chr12-10629593-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_018423.3(STYK1):​c.533T>C​(p.Val178Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: STYK1 NM_018423.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.41

Genes affected

STYK1 (HGNC:18889): (serine/threonine/tyrosine kinase 1) Receptor protein tyrosine kinases, like STYK1, play important roles in diverse cellular and developmental processes, such as cell proliferation, differentiation, and survival (Liu et al., 2004 [PubMed 15150103]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STYK1	NM_018423.3	c.533T>C	p.Val178Ala	missense_variant	6/11	ENST00000075503.8	NP_060893.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STYK1	ENST00000075503.8	c.533T>C	p.Val178Ala	missense_variant	6/11	1	NM_018423.3	ENSP00000075503	P1
STYK1	ENST00000542924.1	c.47T>C	p.Val16Ala	missense_variant	1/2	2		ENSP00000443760

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461890 Hom.: 0 Cov.: 34 AF XY: 0.00000688 AC XY: 5 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

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: 0.0000144

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Dec 18, 2023

The c.533T>C (p.V178A) alteration is located in exon 6 (coding exon 4) of the STYK1 gene. This alteration results from a T to C substitution at nucleotide position 533, causing the valine (V) at amino acid position 178 to be replaced by an alanine (A). 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	0.31
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.76
Sift	Benign	0.090	T
Sift4G	Benign	0.072	T
Polyphen		0.99	D
Vest4		0.57
MutPred		0.88		Loss of sheet (P = 0.0817);
MVP		0.90
MPC		0.74
ClinPred		0.88	D
GERP RS		5.6
Varity_R		0.24
gMVP		0.55

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: chr12-10782192;