NM_152594.3:c.973C>T

Variant names:

• chr15-38351302-C-T
• rs1057518683
• NM_152594.3:c.973C>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_152594.3(SPRED1):​c.973C>T​(p.Arg325*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SPRED1 NM_152594.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.44

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.271 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-38351302-C-T is Pathogenic according to our data. Variant chr15-38351302-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 374301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-38351302-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPRED1	NM_152594.3	c.973C>T	p.Arg325*	stop_gained	Exon 7 of 7	ENST00000299084.9	NP_689807.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPRED1	ENST00000299084.9	c.973C>T	p.Arg325*	stop_gained	Exon 7 of 7	1	NM_152594.3	ENSP00000299084.4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152044 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461816 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727206

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152044 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74240

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Legius syndrome Pathogenic:2

Nov 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg325*) in the SPRED1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 120 amino acid(s) of the SPRED1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Legius syndrome (PMID: 17704776, 25883013; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 374301). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects SPRED1 function (PMID: 17704776). This variant disrupts a region of the SPRED1 protein in which other variant(s) (p.Gly385Ilefs*20, p.Arg349Glyfs*11) have been determined to be pathogenic (PMID: 17704776, 21089071, 21649642). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Apr 10, 2015

Baylor Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This de novo pathogenic variant has been previously reported as disease-causing [PMID 17704776] and was found in our laboratory in a 6 month old female with delayed motor milestones, generalized hypotonia with tracheostomy, micrognathia, camptodactyly and overriding toes, failure to thrive, patent foramen ovale, and hemangioma on the left hand. A homozygous pathogenic variant in MEGF10 (NM_032446.2, c.1557delA) was reported in the same individual. -

Male infertility with spermatogenesis disorder Pathogenic:1

Dec 01, 2023

Laan Lab, Human Genetics Research Group, University of Tartu

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

In addition, the same case carried one additional variant: TP63 c.1283C>T p.P428L, indicating a digenic effect. -

Cardiovascular phenotype Pathogenic:1

May 05, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R325* pathogenic mutation (also known as c.973C>T), located in coding exon 7 of the SPRED1 gene, results from a C to T substitution at nucleotide position 973. This changes the amino acid from an arginine to a stop codon within coding exon 7. This mutation was originally identified in a patient with neurofibromatosis 1 (NF1)-like phenotype (Brems H et al. Nat. Genet., 2007 Sep;39:1120-6) and subsequently reported in multiple patients with NF1 features (Messiaen L et al. JAMA, 2009 Nov;302:2111-8; Benelli E et al. Ital J Pediatr, 2015 Feb;41:8). In addition, this mutation results in loss of the Sprouty domain, and R325* mutant protein lacked the ability to negatively regulate the Ras-MAPK pathway (Brems H et al. Nat. Genet., 2007 Sep;39:1120-6). This alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.95	D
Vest4		0.77
GERP RS		5.0

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: rs1057518683; hg19: chr15-38643503;