rs1060502505

Positions:

• chr15-38324807-C-A
• chr15-38324807-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152594.3(SPRED1):​c.421C>A​(p.Gln141Lys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SPRED1 NM_152594.3 missense, splice_region
• Scores: Splicing: ADA: 0.008420
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.70

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.140457).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPRED1	NM_152594.3	c.421C>A	p.Gln141Lys	missense_variant, splice_region_variant	4/7	ENST00000299084.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPRED1	ENST00000299084.9	c.421C>A	p.Gln141Lys	missense_variant, splice_region_variant	4/7	1	NM_152594.3	P1
SPRED1	ENST00000561317.1	c.358C>A	p.Gln120Lys	missense_variant, splice_region_variant	5/6	4
SPRED1	ENST00000561205.1	n.759C>A		splice_region_variant, non_coding_transcript_exon_variant	4/5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1459504 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 725932

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.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Legius syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 18, 2016

In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SPRED1-related disease. This sequence change replaces glutamine with lysine at codon 141 of the SPRED1 protein (p.Gln141Lys). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and lysine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.22	T;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.048
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.81	L;.
MutationTaster	Benign	0.58	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.88	N;N
REVEL	Benign	0.17
Sift	Benign	0.39	T;T
Sift4G	Benign	0.97	T;T
Polyphen		0.0010	B;.
Vest4		0.28
MutPred		0.25		Gain of ubiquitination at Q141 (P = 0.0014);.;
MVP		0.74
MPC		0.44
ClinPred		0.38	T
GERP RS		4.0
Varity_R		0.22
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0084
dbscSNV1_RF	Benign	0.13
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-38617008; COSMIC: COSV100136476;