chr17-63704443-C-T

Variant names:

• chr17-63704443-C-T
• rs754413346
• NM_001003787.4:c.998G>A

Variant summary

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

The NM_001003787.4(STRADA):​c.998G>A​(p.Arg333Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000317 in 1,610,204 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R333W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: STRADA NM_001003787.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.33
• 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: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

ENSG00000125695 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30428582).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STRADA	NM_001003787.4	c.998G>A	p.Arg333Gln	missense_variant	Exon 11 of 13	ENST00000336174.12	NP_001003787.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STRADA	ENST00000336174.12	c.998G>A	p.Arg333Gln	missense_variant	Exon 11 of 13	1	NM_001003787.4	ENSP00000336655.6
ENSG00000125695	ENST00000580553.1	n.*912G>A		non_coding_transcript_exon_variant	Exon 10 of 12	5		ENSP00000464100.1
ENSG00000125695	ENST00000580553.1	n.*912G>A		3_prime_UTR_variant	Exon 10 of 12	5		ENSP00000464100.1

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 150906 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000659

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000527 AC: 13 AN: 246506 AF XY: 0.0000373

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000233

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000360

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000336 AC: 49 AN: 1459298 Hom.: 0 Cov.: 45 AF XY: 0.0000262 AC XY: 19 AN XY: 725734

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.000179 AC: 8 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52134

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1111062

Other (OTH) AF: 0.00 AC: 0 AN: 60280

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 150906 Hom.: 0 Cov.: 31 AF XY: 0.0000272 AC XY: 2 AN XY: 73636

African (AFR) AF: 0.00 AC: 0 AN: 40970

American (AMR) AF: 0.0000659 AC: 1 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5080

South Asian (SAS) AF: 0.00 AC: 0 AN: 4782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10476

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67678

Other (OTH) AF: 0.00 AC: 0 AN: 2058

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Polyhydramnios, megalencephaly, and symptomatic epilepsy Uncertain:1

Jul 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 575275). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 333 of the STRADA protein (p.Arg333Gln). This variant is present in population databases (no rsID available, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with STRADA-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.057	.;.;T;.;.;.;.;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D;.;D;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.89	.;.;L;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		7.3
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.29	.;.;N;.;N;.;.;N;N;.;.;.;.;.;.
REVEL	Benign	0.16
Sift	Benign	0.14	.;.;T;.;T;.;.;D;T;.;.;.;.;.;.
Sift4G	Benign	0.41	.;.;T;.;T;.;.;T;T;.;.;.;.;T;.
Polyphen		0.99, 0.99, 0.98	.;D;D;D;.;.;.;.;D;.;.;.;.;.;.
Vest4		0.69, 0.68, 0.67, 0.55, 0.70
MutPred		0.31		.;.;Loss of catalytic residue at R333 (P = 0.087);.;.;.;.;.;.;.;.;Loss of catalytic residue at R333 (P = 0.087);Loss of catalytic residue at R333 (P = 0.087);.;.;
MVP		0.78
MPC		1.3
ClinPred		0.43	T
GERP RS		4.9
PromoterAI		0.011	Neutral
Varity_R		0.54
gMVP		0.51
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs754413346; hg19: chr17-61781803;