15-38253188-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_152594.3(SPRED1):c.3G>A(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 Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SPRED1 NM_152594.3 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.92

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: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_152594.3 (SPRED1) was described as [Likely_pathogenic] in ClinVar as 930640
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-38253188-G-A is Pathogenic according to our data. Variant chr15-38253188-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 854050.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPRED1	NM_152594.3	c.3G>A	p.Met1?	start_lost	1/7	ENST00000299084.9
SPRED1	XM_005254202.4	c.3G>A	p.Met1?	start_lost	1/8
SPRED1	XM_047432199.1	c.-161G>A		5_prime_UTR_variant	1/9
SPRED1	XM_047432200.1	c.-125G>A		5_prime_UTR_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPRED1	ENST00000299084.9	c.3G>A	p.Met1?	start_lost	1/7	1	NM_152594.3	P1
SPRED1	ENST00000561317.1	c.-125G>A		5_prime_UTR_variant	1/6	4
SPRED1	ENST00000561205.1	n.341G>A		non_coding_transcript_exon_variant	1/5	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1428004 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 706948

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Legius syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 23, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 854050). 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. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the SPRED1 mRNA. The next in-frame methionine is located at codon 22. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.13	D
MutationTaster	Benign	1.0	D
PROVEAN	Benign	-1.2	N
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.033	D
Polyphen		0.53	P
Vest4		0.94
MutPred		1.0		Gain of glycosylation at S2 (P = 0.0674);
MVP		0.97
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.94
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1324903101; hg19: chr15-38545389;