rs1555392598

chr15-38349444-T-C

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.18

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 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/exons	MANE	UniProt
SPRED1	NM_152594.3	c.605T>C	p.Leu202Ser	missense_variant	6/7	ENST00000299084.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPRED1	ENST00000299084.9	c.605T>C	p.Leu202Ser	missense_variant	6/7	1	NM_152594.3	P1

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

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

May 30, 2017

- -

Legius syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 18, 2022

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. 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. ClinVar contains an entry for this variant (Variation ID: 445692). This variant has not been reported in the literature in individuals affected with SPRED1-related conditions. This variant is not present in population databases (gnomAD no frequency). 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). -

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
MutationTaster	Benign	0.63	D
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

Other links and lift over

dbSNP: rs1555392598; hg19: chr15-38641645;