rs7180446

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_152594.3(SPRED1):c.424-8C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.882 in 1,612,586 control chromosomes in the GnomAD database, including 629,837 homozygotes. 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 Benign (★★).

Frequency

Genomes: 𝑓 0.82 ( 52403 hom., cov: 30)

Exomes 𝑓: 0.89 ( 577434 hom. )

Consequence

SPRED1
NM_152594.3 splice_region, intron

Scores

Splicing: ADA: 0.005107

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.863

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 15-38339729-C-A is Benign according to our data. Variant chr15-38339729-C-A is described in ClinVar as [Benign]. Clinvar id is 41453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-38339729-C-A is described in Lovd as [Benign].

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 linkuse as main transcript	c.424-8C>A		splice_region_variant, intron_variant		ENST00000299084.9	NP_689807.1	Q7Z699

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPRED1	ENST00000299084.9 linkuse as main transcript	c.424-8C>A		splice_region_variant, intron_variant		1	NM_152594.3	ENSP00000299084.4		Q7Z699
SPRED1	ENST00000561317.1 linkuse as main transcript	c.361-8C>A		splice_region_variant, intron_variant		4		ENSP00000453680.1		H0YMN8

Frequencies

GnomAD3 genomes

AF:

0.824

AC:

125209

AN:

151918

Hom.:

52390

Cov.:

show subpopulations

Gnomad AFR

AF:

0.663

Gnomad AMI

AF:

0.748

Gnomad AMR

AF:

0.841

Gnomad ASJ

AF:

0.902

Gnomad EAS

AF:

0.792

Gnomad SAS

AF:

0.879

Gnomad FIN

AF:

0.934

Gnomad MID

AF:

0.832

Gnomad NFE

AF:

0.897

Gnomad OTH

AF:

0.829

GnomAD3 exomes

AF:

0.865

AC:

217263

AN:

251082

Hom.:

94677

AF XY:

0.873

AC XY:

118505

AN XY:

135722

show subpopulations

Gnomad AFR exome

AF:

0.653

Gnomad AMR exome

AF:

0.826

Gnomad ASJ exome

AF:

0.909

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:

1296882

AN:

1460550

Hom.:

577434

Cov.:

AF XY:

0.889

AC XY:

645933

AN XY:

726618

show subpopulations

Gnomad4 AFR exome

AF:

0.646

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:

0.824

AC:

125273

AN:

152036

Hom.:

52403

Cov.:

AF XY:

0.826

AC XY:

61370

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.663

Gnomad4 AMR

AF:

0.842

Gnomad4 ASJ

AF:

0.902

Gnomad4 EAS

AF:

0.792

Gnomad4 SAS

AF:

0.879

Gnomad4 FIN

AF:

0.934

Gnomad4 NFE

AF:

0.897

Gnomad4 OTH

AF:

0.822

Alfa

AF:

0.878

Hom.:

95124

Bravo

AF:

0.805

Asia WGS

AF:

0.794

AC:

2764

AN:

3478

EpiCase

AF:

0.889

EpiControl

AF:

0.886

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 10, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 14, 2012	424-8C>A in intron 4 of SPRED1: This variant is not expected to have clinical si gnificance because it has been identified in 90% (6302/7020) of European America n chromosomes and 69% (2574/3738) of African American chromosomes from a broad p opulation by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EV S/; dbSNP rs7180446). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Legius syndrome

Benign:6

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
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	Genome-Nilou Lab	Jul 15, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 17, 2017	Variant summary: The SPRED1 c.424-8C>A variant involves the alteration of a non-conserved intronic nucleotide. Mutation taster predicts a benign outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 104727/121254 control chromosomes (45629 homozygotes) from ExAC at a frequency of 0.8636993 at a frequency of 0.8636993, which is approximately 345479 times the estimated maximal expected allele frequency of a pathogenic SPRED1 variant (0.0000025), therefore this variant is a benign common polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

3.9

DANN

Benign

0.67

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0051

dbscSNV1_RF

Benign

0.082

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over