rs7179118

Variant names:

• chr15-38339719-G-A
• rs7179118
• NM_152594.3:c.424-18G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-38339719-G-A
• chr15-38339719-G-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.424-18G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 1,610,272 control chromosomes in the GnomAD database, including 49,718 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.23 (4372 hom., cov: 32)
  • Exomes 𝑓: 0.24 (45346 hom.)
• Consequence: SPRED1 NM_152594.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.0500
• Publications: 5 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 15-38339719-G-A is Benign according to our data. Variant chr15-38339719-G-A is described in ClinVar as Benign. ClinVar VariationId is 41452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPRED1	NM_152594.3	c.424-18G>A		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.424-18G>A		intron_variant	Intron 4 of 6	1	NM_152594.3	ENSP00000299084.4
SPRED1	ENST00000561317.1	c.361-18G>A		intron_variant	Intron 5 of 5	4		ENSP00000453680.1

Frequencies

GnomAD3 genomes AF: 0.235 AC: 35643 AN: 151874 Hom.: 4372 Cov.: 32

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.243

Gnomad EAS AF: 0.0326

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.281

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.244

GnomAD2 exomes AF: 0.223 AC: 56008 AN: 250910 AF XY: 0.226

Gnomad AFR exome AF: 0.221

Gnomad AMR exome AF: 0.179

Gnomad ASJ exome AF: 0.252

Gnomad EAS exome AF: 0.0313

Gnomad FIN exome AF: 0.285

Gnomad NFE exome AF: 0.265

Gnomad OTH exome AF: 0.256

GnomAD4 exome AF: 0.244 AC: 356131 AN: 1458280 Hom.: 45346 Cov.: 31 AF XY: 0.243 AC XY: 176195 AN XY: 725568

African (AFR) AF: 0.222 AC: 7423 AN: 33368

American (AMR) AF: 0.184 AC: 8215 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 6407 AN: 26094

East Asian (EAS) AF: 0.0478 AC: 1893 AN: 39628

South Asian (SAS) AF: 0.175 AC: 15064 AN: 86200

European-Finnish (FIN) AF: 0.283 AC: 15078 AN: 53278

Middle Eastern (MID) AF: 0.303 AC: 1742 AN: 5756

European-Non Finnish (NFE) AF: 0.258 AC: 286159 AN: 1108998

Other (OTH) AF: 0.235 AC: 14150 AN: 60266

GnomAD4 genome AF: 0.235 AC: 35655 AN: 151992 Hom.: 4372 Cov.: 32 AF XY: 0.231 AC XY: 17200 AN XY: 74304

African (AFR) AF: 0.229 AC: 9519 AN: 41484

American (AMR) AF: 0.193 AC: 2944 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 842 AN: 3466

East Asian (EAS) AF: 0.0327 AC: 169 AN: 5176

South Asian (SAS) AF: 0.179 AC: 860 AN: 4806

European-Finnish (FIN) AF: 0.281 AC: 2965 AN: 10552

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.260 AC: 17646 AN: 67940

Other (OTH) AF: 0.241 AC: 509 AN: 2110

Alfa AF: 0.253 Hom.: 894

Bravo AF: 0.229

Asia WGS AF: 0.104 AC: 359 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Sep 10, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 15, 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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Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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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

- -

Legius syndrome Benign:5

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

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.424-18G>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing and ESE finder predicts no impact on ESE sites at the locus. However, these predictions have yet to be confirmed by functional studies. This variant was found in the large control database ExAC at a frequency of 0.2265353 (27452/121182 control chromosomes [3368 homozygotes]), which is approximately 90614 times the estimated maximal expected allele frequency of a pathogenic SPRED1 variant (0.0000025), providing very strong evidence that this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. To our knowledge, the variant of interest has not been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

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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	-0.74
CADD	Benign	14
DANN	Benign	0.67
PhyloP100		-0.050
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs7179118; hg19: chr15-38631920; COSMIC: COSV54438533;