15-38349514-C-T

Position:

• chr15-38349514-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 0.504

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 -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/exons	MANE	Protein	UniProt
SPRED1	NM_152594.3	c.675C>T	p.Ser225Ser	synonymous_variant	6/7	ENST00000299084.9	NP_689807.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPRED1	ENST00000299084.9	c.675C>T	p.Ser225Ser	synonymous_variant	6/7	1	NM_152594.3	ENSP00000299084.4

Frequencies

GnomAD3 genomes AF: 0.000757 AC: 115 AN: 151900 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.00116 AC XY: 156 AN XY: 134902

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.: 2 Cov.: 28 AF XY: 0.00112 AC XY: 812 AN XY: 723884

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.: 0 Cov.: 32 AF XY: 0.000781 AC XY: 58 AN XY: 74282

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.: 0

Bravo AF: 0.000854

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

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.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. -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 23, 2016	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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	SPRED1: BP4, BS1 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Legius syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 23, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 08, 2015	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. -

SPRED1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2019

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

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 24, 2014

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

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 13, 2021

- -

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

Other links and lift over

dbSNP: rs144764225; hg19: chr15-38641715; COSMIC: COSV100136142;