rs1555699052

Variant names:

• chr17-63710782-C-T
• rs1555699052
• NM_001003787.4:c.403G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The ENST00000336174.12(STRADA):​c.403G>A​(p.Ala135Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: STRADA ENST00000336174.12 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.67
• Publications: 0 publications found

Genes affected

STRADA (HGNC:30172): (STE20 related adaptor alpha) The protein encoded by this gene contains a STE20-like kinase domain, but lacks several residues that are critical for catalytic activity, so it is termed a 'pseudokinase'. The protein forms a heterotrimeric complex with serine/threonine kinase 11 (STK11, also known as LKB1) and the scaffolding protein calcium binding protein 39 (CAB39, also known as MO25). The protein activates STK11 leading to the phosphorylation of both proteins and excluding STK11 from the nucleus. The protein is necessary for STK11-induced G1 cell cycle arrest. A mutation in this gene has been shown to result in polyhydramnios, megalencephaly, and symptomatic epilepsy (PMSE) syndrome. Multiple transcript variants encoding different isoforms have been found for this gene. Additional transcript variants have been described but their full-length nature is not known. [provided by RefSeq, Sep 2009]

STRADA Gene-Disease associations (from GenCC):

• polyhydramnios, megalencephaly, and symptomatic epilepsy

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

ENSG00000125695 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-63710782-C-T is Pathogenic according to our data. Variant chr17-63710782-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 433133.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.24352261). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000336174.12. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STRADA	NM_001003787.4	MANE Select	c.403G>A	p.Ala135Thr	missense	Exon 7 of 13	NP_001003787.1
	STRADA	NM_001363786.1		c.379G>A	p.Ala127Thr	missense	Exon 7 of 13	NP_001350715.1
	STRADA	NM_001363787.1		c.316G>A	p.Ala106Thr	missense	Exon 5 of 11	NP_001350716.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STRADA	ENST00000336174.12	TSL:1 MANE Select	c.403G>A	p.Ala135Thr	missense	Exon 7 of 13	ENSP00000336655.6
	STRADA	ENST00000375840.9	TSL:1	c.229G>A	p.Ala77Thr	missense	Exon 6 of 12	ENSP00000365000.4
	STRADA	ENST00000392950.9	TSL:1	c.292G>A	p.Ala98Thr	missense	Exon 5 of 9	ENSP00000376677.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Self-limited epilepsy with centrotemporal spikes (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	0.00043	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Benign	0.94
DEOGEN2	Benign	0.046	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.082
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.065	N
PhyloP100		4.7
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.17
Sift	Benign	1.0	T
Sift4G	Benign	0.81	T
Polyphen		0.14	B
Vest4		0.43
MutPred		0.53		Gain of sheet (P = 0.1539)
MVP		0.74
MPC		1.1
ClinPred		0.83	D
GERP RS		5.0
Varity_R		0.58
gMVP		0.60
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555699052; hg19: chr17-61788142;