chr17-63723317-G-A

Variant names:

• chr17-63723317-G-A
• rs143559168
• NM_001003787.4:c.104C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001003787.4(STRADA):​c.104C>T​(p.Pro35Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000866 in 1,614,164 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P35P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00079 (3 hom.)
• Consequence: STRADA NM_001003787.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.87
• Publications: 5 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 -16 ACMG points.

• BP6: Variant 17-63723317-G-A is Benign according to our data. Variant chr17-63723317-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 536764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00163 (248/152284) while in subpopulation AFR AF = 0.00436 (181/41554). AF 95% confidence interval is 0.00384. There are 1 homozygotes in GnomAd4. There are 114 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.104C>T	p.Pro35Leu	missense	Exon 4 of 13	NP_001003787.1	Q7RTN6-1
	STRADA	NM_001363786.1		c.80C>T	p.Pro27Leu	missense	Exon 4 of 13	NP_001350715.1
	STRADA	NM_001363788.1		c.104C>T	p.Pro35Leu	missense	Exon 4 of 13	NP_001350717.1	A0A1W2PPG2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STRADA	ENST00000336174.12	TSL:1 MANE Select	c.104C>T	p.Pro35Leu	missense	Exon 4 of 13	ENSP00000336655.6	Q7RTN6-1
	STRADA	ENST00000375840.9	TSL:1	c.-52+3321C>T		intron	N/A	ENSP00000365000.4	Q7RTN6-5
	STRADA	ENST00000392950.9	TSL:1	c.12+5041C>T		intron	N/A	ENSP00000376677.4	Q7RTN6-2

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 247 AN: 152166 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000808

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000608 AC: 153 AN: 251482 AF XY: 0.000567

Gnomad AFR exome AF: 0.00455

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000668

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000787 AC: 1150 AN: 1461880 Hom.: 3 Cov.: 30 AF XY: 0.000759 AC XY: 552 AN XY: 727242

African (AFR) AF: 0.00529 AC: 177 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000834 AC: 927 AN: 1112004

Other (OTH) AF: 0.000613 AC: 37 AN: 60394

GnomAD4 genome AF: 0.00163 AC: 248 AN: 152284 Hom.: 1 Cov.: 32 AF XY: 0.00153 AC XY: 114 AN XY: 74462

African (AFR) AF: 0.00436 AC: 181 AN: 41554

American (AMR) AF: 0.000327 AC: 5 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000808 AC: 55 AN: 68034

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.000894 Hom.: 0

Bravo AF: 0.00169

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000610 AC: 74

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (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	0.073
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	23
DANN	Benign	0.93
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.094
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.9
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.079
Sift	Benign	0.14	T
Sift4G	Benign	0.20	T
Polyphen		0.0020	B
Vest4		0.29
MVP		0.51
MPC		0.44
ClinPred		0.018	T
GERP RS		6.1
Varity_R		0.14
gMVP		0.55
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.24		Position offset: 9

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

Other links and lift over

dbSNP: rs143559168; hg19: chr17-61800677;