rs1555392759

Positions:

• chr15-38351249-ACT-A

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.Ser308fs) 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/exons	MANE	Protein	UniProt
SPRED1	NM_152594.3	c.923_924delCT	p.Ser308fs	frameshift_variant	7/7	ENST00000299084.9	NP_689807.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPRED1	ENST00000299084.9	c.923_924delCT	p.Ser308fs	frameshift_variant	7/7	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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 13, 2019

For these reasons, this variant has been classified as Pathogenic. 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 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). This variant is not present in population databases (ExAC no frequency). 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. -

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;