rs7182445

Variant names:

• chr15-38322324-G-A
• rs7182445
• NM_152594.3:c.291G>A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_152594.3(SPRED1):​c.291G>A​(p.Lys97Lys) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15 O:1
• Conservation: PhyloP100: 3.71

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 -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 rank	MANE	Protein	UniProt
SPRED1	NM_152594.3	c.291G>A	p.Lys97Lys	synonymous_variant	Exon 3 of 7	ENST00000299084.9	NP_689807.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPRED1	ENST00000299084.9	c.291G>A	p.Lys97Lys	synonymous_variant	Exon 3 of 7	1	NM_152594.3	ENSP00000299084.4
SPRED1	ENST00000561317.1	c.228G>A	p.Lys76Lys	synonymous_variant	Exon 4 of 6	4		ENSP00000453680.1
SPRED1	ENST00000561205.1	n.629G>A		non_coding_transcript_exon_variant	Exon 3 of 5	5

Frequencies

GnomAD3 genomes AF: 0.824 AC: 125286 AN: 151994 Hom.: 52426 Cov.: 31

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

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.: 53 AF XY: 0.889 AC XY: 646274 AN XY: 727112

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.: 31 AF XY: 0.826 AC XY: 61407 AN XY: 74352

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:15 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Legius syndrome Benign:6 Other:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

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 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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. -

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:5

Mar 14, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 10, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

Apr 17, 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.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. -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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	-0.37
CADD	Benign	10
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

Other links and lift over

dbSNP: rs7182445; hg19: chr15-38614525; COSMIC: COSV54434943;