Variant 15-38324807-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_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

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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 linkuse as main transcript	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
SPRED1	ENST00000299084.9 linkuse as main transcript	c.421C>A	p.Gln141Lys	missense_variant, splice_region_variant	4/7	1	NM_152594.3	P1
SPRED1	ENST00000561317.1 linkuse as main transcript	c.358C>A	p.Gln120Lys	missense_variant, splice_region_variant	5/6	4
SPRED1	ENST00000561205.1 linkuse as main transcript	n.759C>A		splice_region_variant, non_coding_transcript_exon_variant	4/5	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1459504

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

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

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.22

T;T

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.048

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.018

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.81

L;.

MutationTaster

Benign

0.58

PrimateAI

Benign

0.36

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over