rs1555392609

Variant names:

• chr15-38349515-C-T
• rs1555392609
• NM_152594.3:c.676C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_152594.3(SPRED1):​c.676C>T​(p.Gln226*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPRED1 NM_152594.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.53
• Publications: 0 publications found

Genes affected

SPRED1 (HGNC:20249): (sprouty related EVH1 domain containing 1) The protein encoded by this gene is a member of the Sprouty family of proteins and is phosphorylated by tyrosine kinase in response to several growth factors. The encoded protein can act as a homodimer or as a heterodimer with SPRED2 to regulate activation of the MAP kinase cascade. Defects in this gene are a cause of neurofibromatosis type 1-like syndrome (NFLS). [provided by RefSeq, Jul 2008]

SPRED1 Gene-Disease associations (from GenCC):

• Legius syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, ClinGen, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 71 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-38349515-C-T is Pathogenic according to our data. Variant chr15-38349515-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 536686.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPRED1	NM_152594.3	c.676C>T	p.Gln226*	stop_gained	Exon 6 of 7	ENST00000299084.9	NP_689807.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPRED1	ENST00000299084.9	c.676C>T	p.Gln226*	stop_gained	Exon 6 of 7	1	NM_152594.3	ENSP00000299084.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Legius syndrome Pathogenic:1

Aug 29, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. A different truncation (p.Met266Valfs*4) that lies downstream of this variant has been determined to be pathogenic (PMID: 17704776, 22751498). This suggests that deletion of this region of the SPRED1 protein is causative of disease. This variant has not been reported in the literature in individuals with SPRED1-related disease. ClinVar contains an entry for this variant (Variation ID: 536686). This sequence change results in a premature translational stop signal in the SPRED1 gene (p.Gln226*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 219 amino acids of the SPRED1 protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.86	D
PhyloP100		3.5
Vest4		0.89
GERP RS		5.2
Mutation Taster		=2/198	disease causing (ClinVar)

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: rs1555392609; hg19: chr15-38641716;