NM_001003787.4:c.998G>C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001003787.4(STRADA):​c.998G>C​(p.Arg333Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,300 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: STRADA NM_001003787.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.33
• 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: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia

ENSG00000125695 (HGNC:):

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage

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.998G>C	p.Arg333Pro	missense	Exon 11 of 13	NP_001003787.1	Q7RTN6-1
	STRADA	NM_001363786.1		c.974G>C	p.Arg325Pro	missense	Exon 11 of 13	NP_001350715.1
	STRADA	NM_001363787.1		c.911G>C	p.Arg304Pro	missense	Exon 9 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.998G>C	p.Arg333Pro	missense	Exon 11 of 13	ENSP00000336655.6	Q7RTN6-1
	STRADA	ENST00000375840.9	TSL:1	c.824G>C	p.Arg275Pro	missense	Exon 10 of 12	ENSP00000365000.4	Q7RTN6-5
	STRADA	ENST00000392950.9	TSL:1	c.887G>C	p.Arg296Pro	missense	Exon 9 of 9	ENSP00000376677.4	Q7RTN6-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459300 Hom.: 0 Cov.: 45 AF XY: 0.00000138 AC XY: 1 AN XY: 725734

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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

American (AMR) AF: 0.00 AC: 0 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: 0.0000116 AC: 1 AN: 86168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52136

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111062

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Benign	0.93
DEOGEN2	Benign	0.067	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.2	L
PhyloP100		7.3
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.25
Sift	Benign	0.050	D
Sift4G	Benign	0.18	T
Polyphen		0.99	D
Vest4		0.68
MutPred		0.46		Gain of glycosylation at R333 (P = 0.0075)
MVP		0.78
MPC		1.5
ClinPred		0.91	D
GERP RS		4.9
PromoterAI		0.12	Neutral
Varity_R		0.79
gMVP		0.61
Mutation Taster		=19/81	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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;