rs7180446

Variant names:

• chr15-38339729-C-A
• rs7180446
• NM_152594.3:c.424-8C>A

Your query was ambiguous. Multiple possible variants found:

• chr15-38339729-C-A
• chr15-38339729-C-G
• chr15-38339729-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Publications: 16 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 -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 VariationId is 41453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.424-8C>A		splice_region_variant, intron_variant	Intron 4 of 6	ENST00000299084.9	NP_689807.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPRED1	ENST00000299084.9	c.424-8C>A		splice_region_variant, intron_variant	Intron 4 of 6	1	NM_152594.3	ENSP00000299084.4
SPRED1	ENST00000561317.1	c.361-8C>A		splice_region_variant, intron_variant	Intron 5 of 5	4		ENSP00000453680.1

Frequencies

GnomAD3 genomes AF: 0.824 AC: 125209 AN: 151918 Hom.: 52390 Cov.: 30

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

GnomAD2 exomes AF: 0.865 AC: 217263 AN: 251082 AF XY: 0.873

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 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.: 42 AF XY: 0.889 AC XY: 645933 AN XY: 726618

African (AFR) AF: 0.646 AC: 21576 AN: 33398

American (AMR) AF: 0.832 AC: 37194 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.907 AC: 23677 AN: 26110

East Asian (EAS) AF: 0.784 AC: 31063 AN: 39638

South Asian (SAS) AF: 0.892 AC: 76930 AN: 86226

European-Finnish (FIN) AF: 0.933 AC: 49763 AN: 53348

Middle Eastern (MID) AF: 0.840 AC: 4838 AN: 5758

European-Non Finnish (NFE) AF: 0.899 AC: 999047 AN: 1111028

Other (OTH) AF: 0.875 AC: 52794 AN: 60346

GnomAD4 genome AF: 0.824 AC: 125273 AN: 152036 Hom.: 52403 Cov.: 30 AF XY: 0.826 AC XY: 61370 AN XY: 74316

African (AFR) AF: 0.663 AC: 27488 AN: 41444

American (AMR) AF: 0.842 AC: 12845 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.902 AC: 3129 AN: 3470

East Asian (EAS) AF: 0.792 AC: 4090 AN: 5164

South Asian (SAS) AF: 0.879 AC: 4229 AN: 4812

European-Finnish (FIN) AF: 0.934 AC: 9888 AN: 10588

Middle Eastern (MID) AF: 0.830 AC: 244 AN: 294

European-Non Finnish (NFE) AF: 0.897 AC: 60940 AN: 67974

Other (OTH) AF: 0.822 AC: 1738 AN: 2114

Alfa AF: 0.872 Hom.: 114544

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

Submissions by phenotype

not specified Benign:6

Mar 14, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

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. -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 10, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

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

- -

Legius syndrome Benign:6

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

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

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

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.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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	3.9
DANN	Benign	0.67
PhyloP100		-0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7180446; hg19: chr15-38631930; COSMIC: COSV54434951;