rs1555392791

Positions:

• chr15-38351523-C-CA

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_152594.3(SPRED1):​c.1196dup​(p.Phe400ValfsTer32) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. D398D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SPRED1 NM_152594.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.67

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-38351523-C-CA is Pathogenic according to our data. Variant chr15-38351523-C-CA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 468790.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPRED1	NM_152594.3	c.1196dup	p.Phe400ValfsTer32	frameshift_variant	7/7	ENST00000299084.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPRED1	ENST00000299084.9	c.1196dup	p.Phe400ValfsTer32	frameshift_variant	7/7	1	NM_152594.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Legius syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 03, 2017

While experimental studies have not been performed on this particular variant, it is expected to disrupt the Sprouty related domain of the SPRED1 protein which is necessary for proper function of the SPRED1 protein (PMID: 15683364). Multiple downstream truncations have been reported in individuals affected with neurofibromatosis type 1-like syndrome (NFLS) (PMID: 19920235). This suggests that deletion of this region of the SPRED1 protein is causative of disease. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SPRED1-related disease. This sequence change inserts 1 nucleotide in exon 7 of the SPRED1 mRNA (c.1196dupA), causing a frameshift at codon 400. This creates a premature translational stop signal in the last exon of the SPRED1 mRNA (p.Phe400Valfs*32). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 45 amino acids of the SPRED1 protein. In summary, this variant is a novel truncation located in the last exon of SPRED1, upstream of truncations that have been reported in affected individuals, and located in a functionally important region of the protein. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555392791; hg19: chr15-38643724;