15-38349514-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_152594.3(SPRED1):c.675C>T(p.Ser225Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,606,344 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00076 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 2 hom. )

Consequence

SPRED1
NM_152594.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 0.504

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.28).

BP6

Variant 15-38349514-C-T is Benign according to our data. Variant chr15-38349514-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 47970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-38349514-C-T is described in Lovd as [Likely_benign]. Variant chr15-38349514-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.504 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000756 (115/152020) while in subpopulation SAS AF= 0.00166 (8/4808). AF 95% confidence interval is 0.000827. There are 0 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 115 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPRED1	NM_152594.3 link	c.675C>T	p.Ser225Ser	synonymous_variant	Exon 6 of 7	ENST00000299084.9	NP_689807.1	Q7Z699

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPRED1	ENST00000299084.9 link	c.675C>T	p.Ser225Ser	synonymous_variant	Exon 6 of 7	1	NM_152594.3	ENSP00000299084.4		Q7Z699

Frequencies

GnomAD3 genomes

AF:

0.000757

AC:

115

AN:

151900

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000363

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00112

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0000947

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000986

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00105

AC:

262

AN:

249546

Hom.:

AF XY:

0.00116

AC XY:

156

AN XY:

134902

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.00149

Gnomad ASJ exome

AF:

0.000697

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00135

Gnomad FIN exome

AF:

0.000140

Gnomad NFE exome

AF:

0.00135

Gnomad OTH exome

AF:

0.000987

GnomAD4 exome

AF:

0.00111

AC:

1615

AN:

1454324

Hom.:

Cov.:

AF XY:

0.00112

AC XY:

812

AN XY:

723884

show subpopulations

Gnomad4 AFR exome

AF:

0.000210

Gnomad4 AMR exome

AF:

0.00144

Gnomad4 ASJ exome

AF:

0.000960

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00119

Gnomad4 FIN exome

AF:

0.0000938

Gnomad4 NFE exome

AF:

0.00116

Gnomad4 OTH exome

AF:

0.00123

GnomAD4 genome

AF:

0.000756

AC:

115

AN:

152020

Hom.:

Cov.:

AF XY:

0.000781

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.000362

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.0000947

Gnomad4 NFE

AF:

0.000971

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000808

Hom.:

Bravo

AF:

0.000854

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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.675C>T (p.Ser225Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 124/117138 control chromosomes from ExAC at a frequency of 0.0010586, which is approximately 423 times the estimated maximal expected allele frequency of a pathogenic SPRED1 variant (0.0000025), therefore this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as benign. Taken together, this variant is classified as Benign. -

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SPRED1: BP4, BS1 -

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 23, 2016

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. -

Legius syndrome

Benign:4

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Aug 23, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:3

Oct 08, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ser225Ser in exon 6 of SPRED1: This variant is not expected to have clinical s ignificance because it has been identified in 0.15% (23/15804) of South Asian ch romosomes and 0.13% (84/64292) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs144764225), does not alter an amino acid residue and is not located within the splice consensus seque nce. -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

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

- -

SPRED1-related disorder

Benign:1

Mar 01, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype

Benign:1

Dec 24, 2014

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. -

Noonan syndrome and Noonan-related syndrome

Benign:1

May 13, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.28

CADD

Benign

9.7

DANN

Benign

0.87

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