rs150880597

Variant names:

• chr17-63703711-C-T
• rs150880597
• NM_001003787.4:c.1184G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

The NM_001003787.4(STRADA):​c.1184G>A​(p.Arg395His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000514 in 1,614,138 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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. R395C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (1 hom.)
• Consequence: STRADA NM_001003787.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.84
• Publications: 4 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05462402).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000368 (56/152270) while in subpopulation NFE AF = 0.000691 (47/68016). AF 95% confidence interval is 0.000534. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.1184G>A	p.Arg395His	missense	Exon 13 of 13	NP_001003787.1	Q7RTN6-1
	STRADA	NM_001363786.1		c.1160G>A	p.Arg387His	missense	Exon 13 of 13	NP_001350715.1
	STRADA	NM_001363787.1		c.1097G>A	p.Arg366His	missense	Exon 11 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.1184G>A	p.Arg395His	missense	Exon 13 of 13	ENSP00000336655.6	Q7RTN6-1
	STRADA	ENST00000375840.9	TSL:1	c.1010G>A	p.Arg337His	missense	Exon 12 of 12	ENSP00000365000.4	Q7RTN6-5
	STRADA	ENST00000392950.9	TSL:1	c.*572G>A		3_prime_UTR	Exon 9 of 9	ENSP00000376677.4	Q7RTN6-2

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.000691

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000358 AC: 90 AN: 251438 AF XY: 0.000383

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000607

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000529 AC: 774 AN: 1461868 Hom.: 1 Cov.: 31 AF XY: 0.000517 AC XY: 376 AN XY: 727238

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.000470 AC: 21 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

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

European-Non Finnish (NFE) AF: 0.000647 AC: 720 AN: 1111994

Other (OTH) AF: 0.000497 AC: 30 AN: 60396

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152270 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74442

African (AFR) AF: 0.0000962 AC: 4 AN: 41568

American (AMR) AF: 0.000327 AC: 5 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000691 AC: 47 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000627 Hom.: 0

Bravo AF: 0.000374

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000371 AC: 45

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	2	-	Polyhydramnios, megalencephaly, and symptomatic epilepsy (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Benign	0.91
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.026
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.8
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.15
Sift	Benign	0.35	T
Sift4G	Benign	0.59	T
Polyphen		0.014	B
Vest4		0.11
MVP		0.86
MPC		0.54
ClinPred		0.040	T
GERP RS		5.0
Varity_R		0.18
gMVP		0.29
Mutation Taster		=80/20	polymorphism

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: rs150880597; hg19: chr17-61781071;