15-38351373-T-C

Variant names:

• chr15-38351373-T-C
• rs3751526
• NM_152594.3:c.1044T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_152594.3(SPRED1):​c.1044T>C​(p.Val348Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.882 in 1,613,954 control chromosomes in the GnomAD database, including 630,003 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (52379 hom., cov: 31)
  • Exomes 𝑓: 0.89 (577624 hom.)
• Consequence: SPRED1 NM_152594.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16 O:1
• Conservation: PhyloP100: 1.23
• Publications: 23 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: Orphanet, Ambry Genetics, Genomics England PanelApp, ClinGen, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 15-38351373-T-C is Benign according to our data. Variant chr15-38351373-T-C is described in ClinVar as Benign. ClinVar VariationId is 41370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.23 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.891 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPRED1	NM_152594.3	c.1044T>C	p.Val348Val	synonymous_variant	Exon 7 of 7	ENST00000299084.9	NP_689807.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPRED1	ENST00000299084.9	c.1044T>C	p.Val348Val	synonymous_variant	Exon 7 of 7	1	NM_152594.3	ENSP00000299084.4

Frequencies

GnomAD3 genomes AF: 0.824 AC: 125195 AN: 151996 Hom.: 52366 Cov.: 31

Gnomad AFR AF: 0.662

Gnomad AMI AF: 0.747

Gnomad AMR AF: 0.841

Gnomad ASJ AF: 0.901

Gnomad EAS AF: 0.792

Gnomad SAS AF: 0.877

Gnomad FIN AF: 0.934

Gnomad MID AF: 0.831

Gnomad NFE AF: 0.896

Gnomad OTH AF: 0.829

GnomAD2 exomes AF: 0.865 AC: 217398 AN: 251258 AF XY: 0.873

Gnomad AFR exome AF: 0.652

Gnomad AMR exome AF: 0.826

Gnomad ASJ exome AF: 0.908

Gnomad EAS exome AF: 0.789

Gnomad FIN exome AF: 0.934

Gnomad NFE exome AF: 0.896

Gnomad OTH exome AF: 0.871

GnomAD4 exome AF: 0.888 AC: 1297707 AN: 1461840 Hom.: 577624 Cov.: 72 AF XY: 0.889 AC XY: 646314 AN XY: 727228

African (AFR) AF: 0.645 AC: 21594 AN: 33474

American (AMR) AF: 0.832 AC: 37207 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.907 AC: 23694 AN: 26132

East Asian (EAS) AF: 0.784 AC: 31110 AN: 39698

South Asian (SAS) AF: 0.892 AC: 76946 AN: 86258

European-Finnish (FIN) AF: 0.933 AC: 49825 AN: 53418

Middle Eastern (MID) AF: 0.841 AC: 4849 AN: 5768

European-Non Finnish (NFE) AF: 0.899 AC: 999655 AN: 1111982

Other (OTH) AF: 0.875 AC: 52827 AN: 60396

GnomAD4 genome AF: 0.823 AC: 125259 AN: 152114 Hom.: 52379 Cov.: 31 AF XY: 0.825 AC XY: 61366 AN XY: 74352

African (AFR) AF: 0.662 AC: 27425 AN: 41448

American (AMR) AF: 0.842 AC: 12852 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.901 AC: 3126 AN: 3468

East Asian (EAS) AF: 0.792 AC: 4101 AN: 5180

South Asian (SAS) AF: 0.877 AC: 4218 AN: 4808

European-Finnish (FIN) AF: 0.934 AC: 9903 AN: 10606

Middle Eastern (MID) AF: 0.829 AC: 242 AN: 292

European-Non Finnish (NFE) AF: 0.896 AC: 60978 AN: 68020

Other (OTH) AF: 0.822 AC: 1734 AN: 2110

Alfa AF: 0.871 Hom.: 125879

Bravo AF: 0.805

Asia WGS AF: 0.795 AC: 2767 AN: 3478

EpiCase AF: 0.890

EpiControl AF: 0.886

ClinVar

Significance: Benign

Submissions summary: Benign:16 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Dec 30, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 14, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 14, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Val348Val in exon 7 of SPRED1: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and it has been identified in 90% (6302/7020) of European American chromosomes and 69% (2574/3738) of African American chromosom es from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs. washington.edu/EVS/; dbSNP rs3751526).

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Legius syndrome Benign:6 Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Apr 18, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The SPRED1 c.1044T>C (p.Val348Val) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. Mutation taster predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect binding of multiple ESE sites. However, no published functional studies are available to confirm these predictions. This variant was found in 104813/121358 control chromosomes (45668 homozygotes) from ExAC at a frequency of 0.8636678; therefore it is a very common polymorphism and allele C is the major allele at this cDNA position. Several clinical diagnostic laboratories/reputable databases have classified this variant as benign. Taken together, this variant is classified as Benign.

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Cardiovascular phenotype Benign:1

Apr 04, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	8.7
DANN	Benign	0.77
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs3751526; hg19: chr15-38643574; COSMIC: COSV54434386;