15-38351014-G-T

Position:

• chr15-38351014-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152594.3(SPRED1):​c.685G>T​(p.Val229Phe) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000685 in 1,459,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SPRED1 NM_152594.3 missense, splice_region
• Scores: Splicing: ADA: 0.6972
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.21

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25883767).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPRED1	NM_152594.3	c.685G>T	p.Val229Phe	missense_variant, splice_region_variant	7/7	ENST00000299084.9	NP_689807.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPRED1	ENST00000299084.9	c.685G>T	p.Val229Phe	missense_variant, splice_region_variant	7/7	1	NM_152594.3	ENSP00000299084.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248426 Hom.: 0 AF XY: 0.00000744 AC XY: 1 AN XY: 134396

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459972 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726258

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Legius syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 18, 2023

This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 229 of the SPRED1 protein (p.Val229Phe). This variant is present in population databases (rs201837340, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with SPRED1-related conditions. ClinVar contains an entry for this variant (Variation ID: 536690). 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. 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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2023

The p.V229F variant (also known as c.685G>T) is located in coding exon 7 of the SPRED1 gene. The valine at codon 229 is replaced by phenylalanine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 7. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	23
DANN	Benign	0.92
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.62	N
REVEL	Uncertain	0.35
Sift	Benign	0.26	T
Sift4G	Benign	0.76	T
Polyphen		0.50	P
Vest4		0.43
MutPred		0.31		Gain of loop (P = 0.0851);
MVP		0.60
MPC		0.64
ClinPred		0.44	T
GERP RS		5.8
Varity_R		0.095
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.70
dbscSNV1_RF	Benign	0.52
SpliceAI score (max)		0.030		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: rs201837340; hg19: chr15-38643215;