SPRED1 p.Thr102Lys

Variant names:

• chr15-38322338-C-A
• rs754706111
• NM_152594.3:c.305C>A
• SPRED1 p.Thr102Lys

Your query was ambiguous. Multiple possible variants found:

• chr15-38322338-C-A
• chr15-38322338-CG-AA

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM2 PM5 PP3_Strong PP5_Moderate

The NM_152594.3(SPRED1):​c.305C>A​(p.Thr102Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 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 (★). ClinVar reports functional evidence for this variant: "SCV001490418: Experimental studies have shown that this missense change affects SPRED1 function (PMID:26635368).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T102M) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SPRED1 NM_152594.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.91
• Publications: 5 publications found

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]

SPRED1 Gene-Disease associations (from GenCC):

• Legius syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Ambry Genetics, Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001490418: Experimental studies have shown that this missense change affects SPRED1 function (PMID: 26635368).
• 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-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1407466.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951
• PP5: Variant 15-38322338-C-A is Pathogenic according to our data. Variant chr15-38322338-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1004532.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152594.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPRED1	NM_152594.3	MANE Select	c.305C>A	p.Thr102Lys	missense	Exon 3 of 7	NP_689807.1	Q7Z699

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPRED1	ENST00000299084.9	TSL:1 MANE Select	c.305C>A	p.Thr102Lys	missense	Exon 3 of 7	ENSP00000299084.4	Q7Z699
	SPRED1	ENST00000881380.1		c.341C>A	p.Thr114Lys	missense	Exon 4 of 8	ENSP00000551439.1
	SPRED1	ENST00000951939.1		c.326C>A	p.Thr109Lys	missense	Exon 4 of 8	ENSP00000621998.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461616 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727108

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111876

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Legius syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.047	D
Varity_R		0.92
gMVP		0.87
Mutation Taster		=5/95	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs754706111;

hg19: chr15-38614539;