rs56163554

Variant names:

• chr17-63714097-C-T
• rs56163554
• NM_001003787.4:c.135G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001003787.4(STRADA):​c.135G>A​(p.Ala45Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0022 in 1,613,312 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (12 hom.)
• Consequence: STRADA NM_001003787.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.242
• Publications: 1 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: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia

ENSG00000125695 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant 17-63714097-C-T is Benign according to our data. Variant chr17-63714097-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212324.
• BP7: Synonymous conserved (PhyloP=0.242 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00175 (266/151996) while in subpopulation SAS AF = 0.00705 (34/4824). AF 95% confidence interval is 0.00518. There are 1 homozygotes in GnomAd4. There are 134 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001003787.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STRADA	NM_001003787.4	MANE Select	c.135G>A	p.Ala45Ala	synonymous	Exon 5 of 13	NP_001003787.1	Q7RTN6-1
	STRADA	NM_001363786.1		c.111G>A	p.Ala37Ala	synonymous	Exon 5 of 13	NP_001350715.1
	STRADA	NM_001363787.1		c.48G>A	p.Ala16Ala	synonymous	Exon 3 of 11	NP_001350716.1	A0A1W2PPJ9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STRADA	ENST00000336174.12	TSL:1 MANE Select	c.135G>A	p.Ala45Ala	synonymous	Exon 5 of 13	ENSP00000336655.6	Q7RTN6-1
	STRADA	ENST00000392950.9	TSL:1	c.24G>A	p.Ala8Ala	synonymous	Exon 3 of 9	ENSP00000376677.4	Q7RTN6-2
	STRADA	ENST00000375840.9	TSL:1	c.-40G>A		5_prime_UTR	Exon 4 of 12	ENSP00000365000.4	Q7RTN6-5

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 266 AN: 151878 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000387

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000788

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00704

Gnomad FIN AF: 0.000666

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00263

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00257 AC: 646 AN: 251348 AF XY: 0.00285

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00208

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00282

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00225 AC: 3288 AN: 1461316 Hom.: 12 Cov.: 31 AF XY: 0.00238 AC XY: 1732 AN XY: 726992

African (AFR) AF: 0.000897 AC: 30 AN: 33460

American (AMR) AF: 0.00217 AC: 97 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.000995 AC: 26 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39674

South Asian (SAS) AF: 0.00619 AC: 534 AN: 86222

European-Finnish (FIN) AF: 0.000281 AC: 15 AN: 53358

Middle Eastern (MID) AF: 0.00850 AC: 49 AN: 5768

European-Non Finnish (NFE) AF: 0.00212 AC: 2360 AN: 1111640

Other (OTH) AF: 0.00290 AC: 175 AN: 60354

GnomAD4 genome AF: 0.00175 AC: 266 AN: 151996 Hom.: 1 Cov.: 32 AF XY: 0.00180 AC XY: 134 AN XY: 74282

African (AFR) AF: 0.000386 AC: 16 AN: 41438

American (AMR) AF: 0.000787 AC: 12 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00705 AC: 34 AN: 4824

European-Finnish (FIN) AF: 0.000666 AC: 7 AN: 10514

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00263 AC: 179 AN: 68002

Other (OTH) AF: 0.00427 AC: 9 AN: 2108

Alfa AF: 0.00231 Hom.: 0

Bravo AF: 0.00162

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00311

EpiControl AF: 0.00356

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	-	not specified (1)
-	-	1	Polyhydramnios, megalencephaly, and symptomatic epilepsy (1)
-	-	1	STRADA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_noAF	Benign	-0.24
CADD	Benign	9.4
DANN	Benign	0.88
PhyloP100		0.24
PromoterAI		0.084	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=293/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs56163554; hg19: chr17-61791457; COSMIC: COSV55562080; COSMIC: COSV55562080;