rs147204964

Positions:

chr15-38299464-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_152594.3(SPRED1):c.124G>A(p.Val42Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000297 in 1,614,004 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00030 ( 4 hom. )

Consequence

SPRED1
NM_152594.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 10.0

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:

SPRED1 (HGNC:):

SPRED1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010319978).

BP6

Variant 15-38299464-G-A is Benign according to our data. Variant chr15-38299464-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47965.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=2}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000296 (45/152278) while in subpopulation SAS AF= 0.00415 (20/4822). AF 95% confidence interval is 0.00275. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 45 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPRED1	NM_152594.3 linkuse as main transcript	c.124G>A	p.Val42Ile	missense_variant	2/7	ENST00000299084.9	NP_689807.1	Q7Z699

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SPRED1	ENST00000299084.9 linkuse as main transcript	c.124G>A	p.Val42Ile	missense_variant	2/7	1	NM_152594.3	ENSP00000299084.4	Q7Z699
SPRED1	ENST00000561317.1 linkuse as main transcript	c.61G>A	p.Val21Ile	missense_variant	3/6	4		ENSP00000453680.1	H0YMN8
SPRED1	ENST00000561205.1 linkuse as main transcript	n.462G>A		non_coding_transcript_exon_variant	2/5	5

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000605

AC:

152

AN:

251158

Hom.:

AF XY:

0.000737

AC XY:

100

AN XY:

135742

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000327

Gnomad SAS exome

AF:

0.00425

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000297

AC:

434

AN:

1461726

Hom.:

Cov.:

AF XY:

0.000375

AC XY:

273

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00151

Gnomad4 SAS exome

AF:

0.00329

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000387

Gnomad4 OTH exome

AF:

0.000580

GnomAD4 genome

AF:

0.000296

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000115

Hom.:

Bravo

AF:

0.000196

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000692

AC:

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 17, 2017	Variant summary: The SPRED1 c.124G>A (p.Val42Ile) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. The variant lies within the WH1/EVH1 domain and the PH domain-like (InterPro). 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in the large control database ExAC in 84/121220 control chromosomes from all ethnicities, but was predominantly observed in the South Asian subpopulation at a frequency of 0.003998 (66/16508 with 2 homozygotes). This frequency is about 1599 times the estimated maximal expected allele frequency of a pathogenic SPRED1 variant (0.0000025), which is very strong evidence that this is likely a benign polymorphism found primarily in the populations of South Asian origin. Multiple publications have identified the variant in patient populations, with one study showing lack of cosegregation due to an unaffected mother transmitting the allele to her affected daughter (Hirata_JBC_2016). Multiple clinical diagnostic laboratories/reputable databases have classified this variant with conflicting interpretations (uncertain significance and likely benign); however, both reports in ClinVar used the ESP database during interpretation, where the variant had not been identified or identified at a very low frequency. The ExAC database, which is approximately 10 times larger than the ESP, shows a relatively high frequency of the variant, including homozygotes in the South Asian subpopulation, strongly supporting this variant as a benign polymorphism. LMM describes a Noonan-syndrome spectrum patient in their lab who was found to carry the variant, along with a de novo BRAF variant, and an unaffected parent also carried the variant of interest, further evidence for the benign nature of the variant. Taken together, this variant is classified as benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Reported in individuals with multiple cafe-au-lait macules, however, one individual also harbored a pathogenic variant in the NF2 gene and inheritance from an unaffected parent was seen in another individual; the authors felt V42I was benign (Hirata et al., 2016); Reported in individuals with multiple cafe-au-lait macules; authors do not classify the variant (Spencer et al., 2011); This variant is associated with the following publications: (PMID: 24469042, 24334617, 22753041, 31401120, 26635368, 21548021) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	SPRED1: PM5, BS1, BS2 -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 26, 2012

Val42Ile in exon 02 of SPRED1: The Val42Ile variant in SPRED1 was reported in on e individual with Legius syndrome (Spencer 2011). Furthermore, this variant was identified in one individual with clinical features within the Noonan spectrum b y our laboratory but was also found in an unaffected parent. However, this prob and also carried a BRAF variant that likely occurred de novo because it was not found in either parent of the proband. In addition, this variant has been identi fied in 0.07% (3/4400) of African American chromosomes from a broad population b y the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP r s147204964). Computational analyses (biochemical amino acid properties, conserv ation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or agai nst an impact to the protein. In summary, the Val42Ile variant is likely benign. -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 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. -

Legius syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Noonan syndrome and Noonan-related syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 14, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.019

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.67

D;T

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.010

T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

M;.

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.88

N;N

REVEL

Uncertain

0.61

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.66

MVP

0.92

MPC

0.99

ClinPred

0.072

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.71

gMVP

0.46

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

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