rs1412213561

chr15-38322254-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_152594.3(SPRED1):c.221G>T(p.Cys74Phe) variant causes a missense change involving the alteration of a conserved nucleotide. 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 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: 10.0

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPRED1	NM_152594.3	c.221G>T	p.Cys74Phe	missense_variant	3/7	ENST00000299084.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPRED1	ENST00000299084.9	c.221G>T	p.Cys74Phe	missense_variant	3/7	1	NM_152594.3	P1
SPRED1	ENST00000561317.1	c.158G>T	p.Cys53Phe	missense_variant	4/6	4
SPRED1	ENST00000561205.1	n.559G>T		non_coding_transcript_exon_variant	3/5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 10, 2023

Variant summary: SPRED1 c.221G>T (p.Cys74Phe) results in a non-conservative amino acid change located in the WH1/EVH1 domain (IPR000697) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251148 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.221G>T has been reported in the literature in a proband affected with Neurofibromatosis Type 1-Like Syndrome (Legius Syndrome) and in the proband's asymptomatic mother (e.g. Messiaen_2009). These report(s) do not provide unequivocal conclusions about association of the variant with Neurofibromatosis Type 1-Like Syndrome (Legius Syndrome). Two publications report experimental evidence in vitro suggesting the variant does not alter protein function, without evidence to establish effect in disease setting, allowing no convincing conclusions about the variant effect (e.g. Messaien_2009, Hirata_2016). The following publications have been ascertained in the context of this evaluation (PMID: 31401120, 26635368, 19920235). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Legius syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 20, 2023

This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 74 of the SPRED1 protein (p.Cys74Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Legius syndrome (PMID: 19920235). ClinVar contains an entry for this variant (Variation ID: 468795). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt SPRED1 function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect SPRED1 function (PMID: 19920235, 26635368). 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	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Pathogenic	29
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-8.9	D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.87
MutPred		0.85		Loss of sheet (P = 0.1158);.;
MVP		0.92
MPC		1.4
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.98
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1412213561; hg19: chr15-38614455;