rs763738243

chr15-38351405-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_152594.3(SPRED1):c.1076T>A(p.Ile359Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SPRED1 NM_152594.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.26

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPRED1	NM_152594.3	c.1076T>A	p.Ile359Asn	missense_variant	7/7	ENST00000299084.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPRED1	ENST00000299084.9	c.1076T>A	p.Ile359Asn	missense_variant	7/7	1	NM_152594.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251224 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135768

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461854 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Legius syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 13, 2017

In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant is present in population databases (rs763738243, ExAC 0.009%) but has not been reported in the literature in individuals with a SPRED1-related disease. This sequence change replaces isoleucine with asparagine at codon 359 of the SPRED1 protein (p.Ile359Asn). The isoleucine residue is moderately conserved and there is a large physicochemical difference between isoleucine and asparagine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.12
Cadd	Uncertain	26
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.74	P
Vest4		0.81
MutPred		0.80		Loss of helix (P = 0.0093);
MVP		0.33
MPC		1.4
ClinPred		0.94	D
GERP RS		6.0
Varity_R		0.76
gMVP		0.76

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: rs763738243; hg19: chr15-38643606;