15-38253186-A-G

Variant summary

Our verdict is Pathogenic. Variant got 21 ACMG points: 21P and 0B. PVS1 PS1_Moderate PM2 PP3 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:2
• 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 21 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_152594.3 (SPRED1) was described as [Pathogenic] in ClinVar as 854050
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• 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/exons	MANE	UniProt
SPRED1	NM_152594.3	c.1A>G	p.Met1?	start_lost	1/7	ENST00000299084.9
SPRED1	XM_005254202.4	c.1A>G	p.Met1?	start_lost	1/8
SPRED1	XM_047432199.1	c.-163A>G		5_prime_UTR_variant	1/9
SPRED1	XM_047432200.1	c.-127A>G		5_prime_UTR_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPRED1	ENST00000299084.9	c.1A>G	p.Met1?	start_lost	1/7	1	NM_152594.3	P1
SPRED1	ENST00000561317.1	c.-127A>G		5_prime_UTR_variant	1/6	4
SPRED1	ENST00000561205.1	n.339A>G		non_coding_transcript_exon_variant	1/5	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Legius syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Sep 12, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP4. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 24, 2017	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
MutationTaster	Benign	1.0	D
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;