rs1555386651

Variant names:

• chr15-38253190-GCGAGGAGACGGCGA-G
• rs1555386651
• NM_152594.3:c.7_20delGAGGAGACGGCGAC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_152594.3(SPRED1):​c.7_20delGAGGAGACGGCGAC​(p.Glu3PhefsTer2) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. E3E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SPRED1 NM_152594.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.92
• 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)

ENSG00000310144 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 137 pathogenic variants in the truncated region.
• PP5: Variant 15-38253190-GCGAGGAGACGGCGA-G is Pathogenic according to our data. Variant chr15-38253190-GCGAGGAGACGGCGA-G is described in ClinVar as [Pathogenic]. Clinvar id is 547789.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.7_20delGAGGAGACGGCGAC	p.Glu3PhefsTer2	frameshift_variant	Exon 1 of 7	ENST00000299084.9	NP_689807.1
SPRED1	XM_005254202.4	c.7_20delGAGGAGACGGCGAC	p.Glu3PhefsTer2	frameshift_variant	Exon 1 of 8		XP_005254259.1
SPRED1	XM_047432199.1	c.-157_-144delGAGGAGACGGCGAC		5_prime_UTR_variant	Exon 1 of 9		XP_047288155.1
SPRED1	XM_047432200.1	c.-121_-108delGAGGAGACGGCGAC		5_prime_UTR_variant	Exon 1 of 8		XP_047288156.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPRED1	ENST00000299084.9	c.7_20delGAGGAGACGGCGAC	p.Glu3PhefsTer2	frameshift_variant	Exon 1 of 7	1	NM_152594.3	ENSP00000299084.4
SPRED1	ENST00000561205.1	n.345_358delGAGGAGACGGCGAC		non_coding_transcript_exon_variant	Exon 1 of 5	5
SPRED1	ENST00000561317.1	c.-121_-108delGAGGAGACGGCGAC		5_prime_UTR_variant	Exon 1 of 6	4		ENSP00000453680.1
ENSG00000310144	ENST00000847565.1	n.95+363_95+376delTCGCCGTCTCCTCG		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Legius syndrome Pathogenic:1

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.9
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555386651; hg19: chr15-38545391;