17-63704443-C-T

Position:

chr17-63704443-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4BS1_Supporting

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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

STRADA
NM_001003787.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.33

Variant links:

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 links:

ENSG00000125695 (HGNC:):

ENSG00000125695 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.30428582).

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000336 (49/1459298) while in subpopulation AMR AF= 0.000179 (8/44662). AF 95% confidence interval is 0.0000887. There are 0 homozygotes in gnomad4_exome. There are 19 alleles in male gnomad4_exome subpopulation. Median coverage is 45. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STRADA	NM_001003787.4 linkuse as main transcript	c.998G>A	p.Arg333Gln	missense_variant	11/13	ENST00000336174.12	NP_001003787.1	Q7RTN6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
STRADA	ENST00000336174.12 linkuse as main transcript	c.998G>A	p.Arg333Gln	missense_variant	11/13	1	NM_001003787.4	ENSP00000336655.6	Q7RTN6-1
ENSG00000125695	ENST00000580553.1 linkuse as main transcript	n.*912G>A		non_coding_transcript_exon_variant	10/12	5		ENSP00000464100.1	J3QR89
ENSG00000125695	ENST00000580553.1 linkuse as main transcript	n.*912G>A		3_prime_UTR_variant	10/12	5		ENSP00000464100.1	J3QR89

Frequencies

GnomAD3 genomes

AF:

0.0000133

AC:

AN:

150906

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000527

AC:

AN:

246506

Hom.:

AF XY:

0.0000373

AC XY:

AN XY:

134000

show subpopulations

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 SAS exome

AF:

0.0000329

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000360

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000336

AC:

AN:

1459298

Hom.:

Cov.:

AF XY:

0.0000262

AC XY:

AN XY:

725734

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000133

AC:

AN:

150906

Hom.:

Cov.:

AF XY:

0.0000272

AC XY:

AN XY:

73636

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000659

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Polyhydramnios, megalencephaly, and symptomatic epilepsy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 06, 2022

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. 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"). ClinVar contains an entry for this variant (Variation ID: 575275). This variant has not been reported in the literature in individuals affected with STRADA-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.02%). 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.095

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.057

.;.;T;.;.;.;.;.;.;.;.;.;.;.;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.88

D;.;D;D;.;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.032

MetaRNN

Benign

0.25

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.58

MutationAssessor

Benign

0.89

.;.;L;.;.;.;.;.;.;.;.;.;.;.;.

PrimateAI

Benign

0.42

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

GERP RS

4.9

Varity_R

0.54

gMVP

0.51

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over