15-38322338-C-G

Variant names:

• chr15-38322338-C-G
• rs754706111
• NM_152594.3:c.305C>G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_152594.3(SPRED1):​c.305C>G​(p.Thr102Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,616 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T102K) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SPRED1 NM_152594.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.91

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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-38322338-C-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 15-38322338-C-G is Pathogenic according to our data. Variant chr15-38322338-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-38322338-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPRED1	NM_152594.3	c.305C>G	p.Thr102Arg	missense_variant	Exon 3 of 7	ENST00000299084.9	NP_689807.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPRED1	ENST00000299084.9	c.305C>G	p.Thr102Arg	missense_variant	Exon 3 of 7	1	NM_152594.3	ENSP00000299084.4
SPRED1	ENST00000561317.1	c.242C>G	p.Thr81Arg	missense_variant	Exon 4 of 6	4		ENSP00000453680.1
SPRED1	ENST00000561205.1	n.643C>G		non_coding_transcript_exon_variant	Exon 3 of 5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461616 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727108

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 Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Jan 15, 2016

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Legius syndrome Pathogenic:1

Jun 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 102 of the SPRED1 protein (p.Thr102Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Legius syndrome (PMID: 19920235; Invitae). ClinVar contains an entry for this variant (Variation ID: 520837). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt SPRED1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SPRED1 function (PMID: 19920235, 21089071, 22751498, 31401120). This variant disrupts the p.Thr102 amino acid residue in SPRED1. Other variant(s) that disrupt this residue have been observed in individuals with SPRED1-related conditions (PMID: 2275304, 21548021, 26635368), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	M;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;.
Vest4		0.91
MutPred		0.88		Gain of solvent accessibility (P = 0.0055);.;
MVP		0.98
MPC		1.2
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.97
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs754706111; hg19: chr15-38614539;