chr15-38351373-T-C

Position:

• chr15-38351373-T-C

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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 id is 41370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-38351373-T-C is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
SPRED1	NM_152594.3	c.1044T>C	p.Val348Val	synonymous_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.1044T>C	p.Val348Val	synonymous_variant	7/7	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

GnomAD3 exomes AF: 0.865 AC: 217398 AN: 251258 Hom.: 94733 AF XY: 0.873 AC XY: 118546 AN XY: 135796

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 SAS exome AF: 0.891

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

Gnomad4 AFR exome AF: 0.645

Gnomad4 AMR exome AF: 0.832

Gnomad4 ASJ exome AF: 0.907

Gnomad4 EAS exome AF: 0.784

Gnomad4 SAS exome AF: 0.892

Gnomad4 FIN exome AF: 0.933

Gnomad4 NFE exome AF: 0.899

Gnomad4 OTH exome AF: 0.875

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

Gnomad4 AFR AF: 0.662

Gnomad4 AMR AF: 0.842

Gnomad4 ASJ AF: 0.901

Gnomad4 EAS AF: 0.792

Gnomad4 SAS AF: 0.877

Gnomad4 FIN AF: 0.934

Gnomad4 NFE AF: 0.896

Gnomad4 OTH AF: 0.822

Alfa AF: 0.878 Hom.: 97829

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

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 14, 2012	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). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 30, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2015	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. -

Legius syndrome Benign:6 Other:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 18, 2017	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. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 04, 2016

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

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