Variant rs7182445 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_152594.3(SPRED1):c.291G>A(p.Lys97=) variant causes a synonymous change. The variant allele was found at a frequency of 0.882 in 1,613,722 control chromosomes in the GnomAD database, including 630,054 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.82 ( 52438 hom., cov: 31)

Exomes 𝑓: 0.89 ( 577616 hom. )

Consequence

SPRED1
NM_152594.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14O:1

Conservation

PhyloP100: 3.71

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BP6

Variant 15-38322324-G-A is Benign according to our data. Variant chr15-38322324-G-A is described in ClinVar as [Benign]. Clinvar id is 41371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-38322324-G-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	UniProt
SPRED1	NM_152594.3 linkuse as main transcript	c.291G>A	p.Lys97=	synonymous_variant	3/7	ENST00000299084.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
SPRED1	ENST00000299084.9 linkuse as main transcript	c.291G>A	p.Lys97=	synonymous_variant	3/7	1	NM_152594.3	P1
SPRED1	ENST00000561317.1 linkuse as main transcript	c.228G>A	p.Lys76=	synonymous_variant	4/6	4
SPRED1	ENST00000561205.1 linkuse as main transcript	n.629G>A		non_coding_transcript_exon_variant	3/5	5

Frequencies

GnomAD3 genomes

AF:

0.824

AC:

125286

AN:

151994

Hom.:

52426

Cov.:

show subpopulations

Gnomad AFR

AF:

0.664

Gnomad AMI

AF:

0.747

Gnomad AMR

AF:

0.841

Gnomad ASJ

AF:

0.902

Gnomad EAS

AF:

0.792

Gnomad SAS

AF:

0.878

Gnomad FIN

AF:

0.933

Gnomad MID

AF:

0.832

Gnomad NFE

AF:

0.897

Gnomad OTH

AF:

0.829

GnomAD3 exomes

AF:

0.865

AC:

217376

AN:

251190

Hom.:

94735

AF XY:

0.873

AC XY:

118536

AN XY:

135752

show subpopulations

Gnomad AFR exome

AF:

0.654

Gnomad AMR exome

AF:

0.826

Gnomad ASJ exome

AF:

0.908

Gnomad EAS exome

AF:

0.790

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:

1297603

AN:

1461610

Hom.:

577616

Cov.:

AF XY:

0.889

AC XY:

646274

AN XY:

727112

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:

125349

AN:

152112

Hom.:

52438

Cov.:

AF XY:

0.826

AC XY:

61407

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.664

Gnomad4 AMR

AF:

0.841

Gnomad4 ASJ

AF:

0.902

Gnomad4 EAS

AF:

0.792

Gnomad4 SAS

AF:

0.878

Gnomad4 FIN

AF:

0.933

Gnomad4 NFE

AF:

0.896

Gnomad4 OTH

AF:

0.822

Alfa

AF:

0.876

Hom.:

108593

Bravo

AF:

0.806

Asia WGS

AF:

0.795

AC:

2766

AN:

3476

EpiCase

AF:

0.889

EpiControl

AF:

0.886

ClinVar

Significance: Benign

Submissions summary: Benign:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Legius syndrome

Benign:6Other:1

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	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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. -

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 14, 2012	Lys97Lys in exon 3 of SPRED1: This variant is not expected to have clinical sign ificance 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% (2576/3738) of African American chromosome s from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.w ashington.edu/EVS/; dbSNP rs7182445). -
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	Eurofins Ntd Llc (ga)	Sep 10, 2015	- -

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.291G>A (p.Lys97Lys) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts loss of the SRp40 and SF2/ASF binding motifs. However, these predictions have yet to be confirmed by functional studies. The variant of interest has been found in a large, broad control population, ExAC in 104831/121368 control chromosomes (45684 homozygotes) at a frequency of 0.863745, which is approximately 345498 times the estimated maximal expected allele frequency of a pathogenic SPRED1 variant (0.0000025), suggesting this variant is likely a benign 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; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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

-0.37

CADD

Benign

DANN

Benign

0.66

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

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