rs1555392598

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_152594.3(SPRED1):​c.605T>C​(p.Leu202Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

SPRED1
NM_152594.3 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.18
Variant links:
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 Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SPRED1NM_152594.3 linkc.605T>C p.Leu202Ser missense_variant Exon 6 of 7 ENST00000299084.9 NP_689807.1 Q7Z699

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SPRED1ENST00000299084.9 linkc.605T>C p.Leu202Ser missense_variant Exon 6 of 7 1 NM_152594.3 ENSP00000299084.4 Q7Z699

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000468
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1
May 30, 2017
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Legius syndrome Uncertain:1
Apr 24, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 202 of the SPRED1 protein (p.Leu202Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SPRED1-related conditions. ClinVar contains an entry for this variant (Variation ID: 445692). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SPRED1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.093
BayesDel_addAF
Benign
-0.0053
T
BayesDel_noAF
Benign
-0.25
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.079
T
Eigen
Benign
-0.045
Eigen_PC
Benign
0.082
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Benign
0.59
T
M_CAP
Benign
0.021
T
MetaRNN
Uncertain
0.45
T
MetaSVM
Benign
-0.86
T
MutationAssessor
Uncertain
2.3
M
PrimateAI
Benign
0.42
T
PROVEAN
Benign
0.0
N
REVEL
Benign
0.16
Sift
Benign
0.061
T
Sift4G
Benign
0.42
T
Polyphen
0.92
P
Vest4
0.62
MutPred
0.40
Loss of catalytic residue at L202 (P = 6e-04);
MVP
0.31
MPC
0.51
ClinPred
0.67
D
GERP RS
5.2
Varity_R
0.055
gMVP
0.50

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555392598; hg19: chr15-38641645; API