15-38299522-G-T

Position:

• chr15-38299522-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_152594.3(SPRED1):​c.182G>T​(p.Arg61Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 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. R61H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: SPRED1 NM_152594.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.20

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.40114853).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPRED1	NM_152594.3	c.182G>T	p.Arg61Leu	missense_variant	2/7	ENST00000299084.9	NP_689807.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPRED1	ENST00000299084.9	c.182G>T	p.Arg61Leu	missense_variant	2/7	1	NM_152594.3	ENSP00000299084.4
SPRED1	ENST00000561317.1	c.119G>T	p.Arg40Leu	missense_variant	3/6	4		ENSP00000453680.1
SPRED1	ENST00000561205.1	n.520G>T		non_coding_transcript_exon_variant	2/5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251124 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135722

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: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461688 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727152

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

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

May 23, 2023

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SPRED1 protein function. ClinVar contains an entry for this variant (Variation ID: 1525083). This variant has not been reported in the literature in individuals affected with SPRED1-related conditions. This variant is present in population databases (rs750686148, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 61 of the SPRED1 protein (p.Arg61Leu). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 20, 2024

The c.182G>T (p.R61L) alteration is located in exon 2 (coding exon 2) of the SPRED1 gene. This alteration results from a G to T substitution at nucleotide position 182, causing the arginine (R) at amino acid position 61 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	0.0040	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;D
Eigen	Benign	0.0030
Eigen_PC	Benign	0.063
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.40	T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.6	L;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.3	N;D
REVEL	Uncertain	0.43
Sift	Benign	0.032	D;T
Sift4G	Benign	0.30	T;T
Polyphen		0.91	P;.
Vest4		0.38
MutPred		0.57		Gain of sheet (P = 0.0827);.;
MVP		0.64
MPC		0.45
ClinPred		0.40	T
GERP RS		2.3
Varity_R		0.24
gMVP		0.67

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: rs750686148; hg19: chr15-38591723;