chr15-38253186-A-G
Variant summary
Our verdict is Pathogenic. Variant got 21 ACMG points: 21P and 0B. PVS1PS1_ModeratePM2PP3PP5_Very_Strong
The NM_152594.3(SPRED1):c.1A>G(p.Met1?) variant causes a start lost change. 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 Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 31)
Consequence
SPRED1
NM_152594.3 start_lost
NM_152594.3 start_lost
Scores
6
5
5
Clinical Significance
Conservation
PhyloP100: 6.46
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 21 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PS1
?
Another start lost variant in NM_152594.3 (SPRED1) was described as [Pathogenic] in ClinVar as 854050
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 15-38253186-A-G is Pathogenic according to our data. Variant chr15-38253186-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 930640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPRED1 | NM_152594.3 | c.1A>G | p.Met1? | start_lost | 1/7 | ENST00000299084.9 | |
SPRED1 | XM_005254202.4 | c.1A>G | p.Met1? | start_lost | 1/8 | ||
SPRED1 | XM_047432199.1 | c.-163A>G | 5_prime_UTR_variant | 1/9 | |||
SPRED1 | XM_047432200.1 | c.-127A>G | 5_prime_UTR_variant | 1/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPRED1 | ENST00000299084.9 | c.1A>G | p.Met1? | start_lost | 1/7 | 1 | NM_152594.3 | P1 | |
SPRED1 | ENST00000561317.1 | c.-127A>G | 5_prime_UTR_variant | 1/6 | 4 | ||||
SPRED1 | ENST00000561205.1 | n.339A>G | non_coding_transcript_exon_variant | 1/5 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Legius syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Sep 12, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP4. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 24, 2017 | The p.Met1? (c.1A>G) variant in SPRED1 has not been previously reported in individuals with clinical features of a RASopathy and was absent from large population studies. However, another variant at this codon (c.2T>C, p.Met1?) has been reported in 1 individual with neurofibromatosis-like syndrome and segregated with disease in 3 affected relatives (Pasmant 2009). The c.2T>C variant results in an novel initiation codon 22 amino acids downstream, which was transcribed into RNA with 21 amino acids lost from the EVH-1 functional domain (Pasmant 2009). If translated, this RNA would be expected to result in a nonfunctional protein (Pasmant 2009) as the EVH-1 functional domain is required for the suppression of ERK (Brems 2007). In summary, although additional studies are required to fully establish its clinical significance, the p.Met1? (c.1A>G) variant is likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
T
MutationTaster
Benign
D
PROVEAN
Benign
N
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Uncertain
D
Polyphen
B
Vest4
MutPred
Gain of glycosylation at S2 (P = 0.1114);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at