rs1057517941
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_152594.3(SPRED1):c.46C>T(p.Arg16Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000186 in 1,613,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
SPRED1
NM_152594.3 stop_gained
NM_152594.3 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 5.03
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 18 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 103 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 15-38299386-C-T is Pathogenic according to our data. Variant chr15-38299386-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 372718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-38299386-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPRED1 | NM_152594.3 | c.46C>T | p.Arg16Ter | stop_gained | 2/7 | ENST00000299084.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPRED1 | ENST00000299084.9 | c.46C>T | p.Arg16Ter | stop_gained | 2/7 | 1 | NM_152594.3 | P1 | |
SPRED1 | ENST00000561317.1 | c.-18C>T | 5_prime_UTR_variant | 3/6 | 4 | ||||
SPRED1 | ENST00000561205.1 | n.384C>T | non_coding_transcript_exon_variant | 2/5 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152064Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461640Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727104
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GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152064Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74272
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Legius syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | May 05, 2023 | PVS1, PS4, PM2, PM6 - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 10, 2020 | Variant summary: SPRED1 c.46C>T (p.Arg16X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251148 control chromosomes (gnomAD). c.46C>T has been reported in the literature in individuals affected with Neurofibromatosis type 1-like Syndrome (Legius Syndrome) (e.g. Messiaen_2009, Pasmant_2009, Sekelska_2017, Spurlock_2009). These data indicate that the variant is likely to be associated with disease. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 04, 2023 | This sequence change creates a premature translational stop signal (p.Arg16*) in the SPRED1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPRED1 are known to be pathogenic (PMID: 17704776). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Legius syndrome (PMID: 19366998, 19443465, 25074460, 28150585). ClinVar contains an entry for this variant (Variation ID: 372718). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 12, 2022 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19443465, 19366998, 21548021, 25074460, 28150585, 29351919, 19920235, 17704776) - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 22, 2014 | The p.R16* pathogenic mutation (also known as c.46C>T) located in coding exon 2 of the SPRED1 gene, results from a C to T substitution at nucleotide position 46. This changes the amino acid from an arginine to a stop codon within coding exon 2. This mutation was seen in both a mother who had cafe au lait spots and punctate dots in her right groin and her daughter who also had cafe au lait spots (Spurlock G, et al. J. Med. Genet. 2009;46(7):431-7). Additionally, this mutation was seen in a father with cafe au lait spots whose son also carried this mutation and had cafe au lait spots, learning disability, and monoblastic acute leukemia (Pasmant E, et al. J. Med. Genet. 2009 Jul; 46(7):425-30). This amino acid position is well conserved in available vertebrate species. In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at