rs1555392759

Variant names:

• chr15-38351249-ACT-A
• rs1555392759
• NM_152594.3:c.923_924delCT

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.923_924delCT​(p.Ser308CysfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPRED1 NM_152594.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.13

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 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-38351249-ACT-A is Pathogenic according to our data. Variant chr15-38351249-ACT-A is described in ClinVar as [Pathogenic]. Clinvar id is 468800.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-38351249-ACT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPRED1	NM_152594.3	c.923_924delCT	p.Ser308CysfsTer4	frameshift_variant	Exon 7 of 7	ENST00000299084.9	NP_689807.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPRED1	ENST00000299084.9	c.923_924delCT	p.Ser308CysfsTer4	frameshift_variant	Exon 7 of 7	1	NM_152594.3	ENSP00000299084.4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Legius syndrome Pathogenic:1

Jan 13, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A different frameshift mutation, c.1149_1152del (p.Gly385Ilefs*20), downstream of this variant has been observed in individuals and families with Legius syndrome (PMID: 17704776, 21089071), which suggests a truncation in the last exon disrupts SPRED1 function and causes disease. This sequence change results in a premature translational stop signal in the SPRED1 gene (p.Ser308Cysfs*4). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 137 amino acids of the SPRED1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in two individuals from the same family affected with neurofibromatosis type 1-like syndrome (NFLS), also known as Legius syndrome (PMID: 19920235). ClinVar contains an entry for this variant (Variation ID: 468800). For these reasons, this variant has been classified as 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: rs1555392759; hg19: chr15-38643450;