15-38351521-G-T

Variant names:

• chr15-38351521-G-T
• rs771480941
• NM_152594.3:c.1192G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_152594.3(SPRED1):​c.1192G>T​(p.Asp398Tyr) 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. D398N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SPRED1 NM_152594.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.99
• 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: ClinGen, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, PanelApp Australia

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• 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.1192G>T	p.Asp398Tyr	missense	Exon 7 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.1192G>T	p.Asp398Tyr	missense	Exon 7 of 7	ENSP00000299084.4	Q7Z699
	SPRED1	ENST00000881380.1		c.1228G>T	p.Asp410Tyr	missense	Exon 8 of 8	ENSP00000551439.1
	SPRED1	ENST00000951939.1		c.1213G>T	p.Asp405Tyr	missense	Exon 8 of 8	ENSP00000621998.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.1	L
PhyloP100		10
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.50
MutPred		0.57		Loss of disorder (P = 0.043)
MVP		0.20
MPC		1.2
ClinPred		0.96	D
GERP RS		5.8
Varity_R		0.43
gMVP		0.51
Mutation Taster		=53/47	polymorphism

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

Other links and lift over

dbSNP: rs771480941; hg19: chr15-38643722;