rs201692618

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_152594.3(SPRED1):c.30C>A(p.Asn10Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000344 in 1,576,894 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N10D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00042 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00034 ( 1 hom. )

Consequence

SPRED1
NM_152594.3 missense, splice_region

Scores

Splicing: ADA: 0.3297

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.85

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007958233).

BP6

Variant 15-38253215-C-A is Benign according to our data. Variant chr15-38253215-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 415718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-38253215-C-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 64 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SPRED1	NM_152594.3 linkuse as main transcript	c.30C>A	p.Asn10Lys	missense_variant, splice_region_variant	1/7	ENST00000299084.9
SPRED1	XM_005254202.4 linkuse as main transcript	c.30C>A	p.Asn10Lys	missense_variant, splice_region_variant	1/8
SPRED1	XM_047432199.1 linkuse as main transcript	c.-134C>A		splice_region_variant, 5_prime_UTR_variant	1/9
SPRED1	XM_047432200.1 linkuse as main transcript	c.-98C>A		splice_region_variant, 5_prime_UTR_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
SPRED1	ENST00000299084.9 linkuse as main transcript	c.30C>A	p.Asn10Lys	missense_variant, splice_region_variant	1/7	1	NM_152594.3	P1
SPRED1	ENST00000561317.1 linkuse as main transcript	c.-98C>A		splice_region_variant, 5_prime_UTR_variant	1/6	4
SPRED1	ENST00000561205.1 linkuse as main transcript	n.368C>A		splice_region_variant, non_coding_transcript_exon_variant	1/5	5

Frequencies

GnomAD3 genomes

AF:

0.000421

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.0150

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000625

AC:

120

AN:

192104

Hom.:

AF XY:

0.000636

AC XY:

AN XY:

102254

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000344

Gnomad ASJ exome

AF:

0.0111

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000173

Gnomad OTH exome

AF:

0.000980

GnomAD4 exome

AF:

0.000336

AC:

479

AN:

1424604

Hom.:

Cov.:

AF XY:

0.000343

AC XY:

242

AN XY:

704970

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000997

Gnomad4 ASJ exome

AF:

0.0137

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000614

Gnomad4 OTH exome

AF:

0.000966

GnomAD4 genome

AF:

0.000420

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.0150

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000806

Hom.:

Bravo

AF:

0.000412

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000309

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Legius syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 17, 2023

Variant summary: SPRED1 c.30C>A (p.Asn10Lys) results in a non-conservative amino acid change located in the WH1/EVH1 domain (IPR000697) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00062 in 192104 control chromosomes. The observed variant frequency is approximately 111 fold of the estimated maximal expected allele frequency for a pathogenic variant in SPRED1 causing Neurofibromatosis Type 1-Like Syndrome (Legius Syndrome) phenotype (5.6e-06), strongly suggesting that the variant is benign. c.30C>A has been reported in the literature in individuals with varying phenotypes including Noonan Syndrome-associated characteristics and Neurofibromatosis Type 1-Like Syndrome (Legius Syndrome) (e.g. Brems_2012, Bhoj_2017, Delio_2015, Hirata_2016). These reports do not provide unequivocal conclusions about association of the variant with Neurofibromatosis Type 1-Like Syndrome (Legius Syndrome). Functional assessment of the variant determined that it does not disrupt the interaction between the SPRED1 EVH1 domain and the NF1 GAP-related domain and that its ERK suppression activity is similar to the wild-type (Hirata_2016). The following publications have been ascertained in the context of this evaluation (PMID: 27763634, 22753041, 26214305, 26635368). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 05, 2020

This variant is associated with the following publications: (PMID: 31401120, 26635368, 22753041) -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Noonan syndrome and Noonan-related syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 27, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.36

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

Eigen

Benign

-0.13

Eigen_PC

Benign

0.031

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.65

M_CAP

Benign

0.030

MetaRNN

Benign

0.0080

MetaSVM

Benign

-0.47

MutationAssessor

Benign

0.34

MutationTaster

Benign

0.99

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.1

REVEL

Benign

0.17

Sift

Benign

0.040

Sift4G

Benign

0.27

Polyphen

0.042

Vest4

0.26

MutPred

0.34

Gain of ubiquitination at N10 (P = 0.0011);

MVP

0.57

MPC

0.45

ClinPred

0.037

GERP RS

3.9

Varity_R

0.19

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.33

dbscSNV1_RF

Benign

0.45

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over