rs1555391039

Variant names:

• chr15-38322320-A-C
• rs1555391039
• NM_152594.3:c.287A>C
• SPRED1 p.Asp96Ala

Your query was ambiguous. Multiple possible variants found:

• chr15-38322320-A-C
• chr15-38322320-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_152594.3(SPRED1):​c.287A>C​(p.Asp96Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D96G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPRED1 NM_152594.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.49
• Publications: 0 publications found

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]

SPRED1 Gene-Disease associations (from GenCC):

• Legius syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Ambry Genetics, Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 11 uncertain in NM_152594.3
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152594.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPRED1	NM_152594.3	MANE Select	c.287A>C	p.Asp96Ala	missense	Exon 3 of 7	NP_689807.1	Q7Z699

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPRED1	ENST00000299084.9	TSL:1 MANE Select	c.287A>C	p.Asp96Ala	missense	Exon 3 of 7	ENSP00000299084.4	Q7Z699
	SPRED1	ENST00000881380.1		c.323A>C	p.Asp108Ala	missense	Exon 4 of 8	ENSP00000551439.1
	SPRED1	ENST00000951939.1		c.308A>C	p.Asp103Ala	missense	Exon 4 of 8	ENSP00000621998.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Legius syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.065	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.5
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.0070	D
Varity_R		0.84
gMVP		0.74
Mutation Taster		=67/33	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1555391039;

hg19: chr15-38614521;