15-38253186-A-G

Variant names:

• chr15-38253186-A-G
• rs1894017295
• NM_152594.3:c.1A>G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_Strong PS1_Moderate PM2 PP5_Very_Strong

The NM_152594.3(SPRED1):​c.1A>G​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SPRED1 NM_152594.3 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.46

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 16 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 5 pathogenic variants. Next in-frame start position is after 22 codons. Genomic position: 38299404. Lost 0.048 part of the original CDS.
• PS1: Another start lost variant in NM_152594.3 (SPRED1) was described as [Likely_pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-38253186-A-G is Pathogenic according to our data. Variant chr15-38253186-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 930640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPRED1	NM_152594.3	c.1A>G	p.Met1?	start_lost	Exon 1 of 7	ENST00000299084.9	NP_689807.1
SPRED1	XM_005254202.4	c.1A>G	p.Met1?	start_lost	Exon 1 of 8		XP_005254259.1
SPRED1	XM_047432199.1	c.-163A>G		5_prime_UTR_variant	Exon 1 of 9		XP_047288155.1
SPRED1	XM_047432200.1	c.-127A>G		5_prime_UTR_variant	Exon 1 of 8		XP_047288156.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPRED1	ENST00000299084.9	c.1A>G	p.Met1?	start_lost	Exon 1 of 7	1	NM_152594.3	ENSP00000299084.4
SPRED1	ENST00000561317	c.-127A>G		5_prime_UTR_variant	Exon 1 of 6	4		ENSP00000453680.1
SPRED1	ENST00000561205.1	n.339A>G		non_coding_transcript_exon_variant	Exon 1 of 5	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Legius syndrome Pathogenic:3

Jul 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the SPRED1 mRNA. The next in-frame methionine is located at codon 22. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with clinical features of Legius syndrome (PMID: 19366998, 32107864; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 930640). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

Sep 12, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP4. -

Jul 24, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Met1? (c.1A>G) variant in SPRED1 has not been previously reported in individuals with clinical features of a RASopathy and was absent from large population studies. However, another variant at this codon (c.2T>C, p.Met1?) has been reported in 1 individual with neurofibromatosis-like syndrome and segregated with disease in 3 affected relatives (Pasmant 2009). The c.2T>C variant results in an novel initiation codon 22 amino acids downstream, which was transcribed into RNA with 21 amino acids lost from the EVH-1 functional domain (Pasmant 2009). If translated, this RNA would be expected to result in a nonfunctional protein (Pasmant 2009) as the EVH-1 functional domain is required for the suppression of ERK (Brems 2007). In summary, although additional studies are required to fully establish its clinical significance, the p.Met1? (c.1A>G) variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	33
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	-0.052	T
PROVEAN	Benign	-1.1	N
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.018	D
Polyphen		0.32	B
Vest4		0.95
MutPred		1.0		Gain of glycosylation at S2 (P = 0.1114);
MVP		0.98
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.95
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.65		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.65		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1894017295; hg19: chr15-38545387;