15-38253211-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_152594.3(SPRED1):c.26A>T(p.Asp9Val) variant causes a missense change. The variant allele was found at a frequency of 0.0003 in 1,578,420 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 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. D9N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00030 ( 2 hom. )

Consequence

SPRED1
NM_152594.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 5.88

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

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

SPRED1 links:

ENSG00000310144 (HGNC:):

ENSG00000310144 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004651457).

BP6

Variant 15-38253211-A-T is Benign according to our data. Variant chr15-38253211-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000256 (39/152164) while in subpopulation SAS AF = 0.0027 (13/4820). AF 95% confidence interval is 0.00159. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 39 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPRED1	NM_152594.3	MANE Select	c.26A>T	p.Asp9Val	missense	Exon 1 of 7	NP_689807.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SPRED1	ENST00000299084.9	TSL:1 MANE Select	c.26A>T	p.Asp9Val	missense	Exon 1 of 7	ENSP00000299084.4
SPRED1	ENST00000561205.1	TSL:5	n.364A>T		non_coding_transcript_exon	Exon 1 of 5
SPRED1	ENST00000561317.1	TSL:4	c.-102A>T		5_prime_UTR	Exon 1 of 6	ENSP00000453680.1

Frequencies

GnomAD3 genomes

AF:

0.000257

AC:

AN:

152046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000680

AC:

133

AN:

195612

AF XY:

0.000786

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000373

Gnomad ASJ exome

AF:

0.00551

Gnomad EAS exome

AF:

0.0000680

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000724

Gnomad OTH exome

AF:

0.000194

GnomAD4 exome

AF:

0.000304

AC:

434

AN:

1426256

Hom.:

Cov.:

AF XY:

0.000373

AC XY:

263

AN XY:

705918

show subpopulations

African (AFR)

AF:

0.0000306

AC:

AN:

32674

American (AMR)

AF:

0.000273

AC:

AN:

40342

Ashkenazi Jewish (ASJ)

AF:

0.00529

AC:

135

AN:

25524

East Asian (EAS)

AF:

0.00

AC:

AN:

37914

South Asian (SAS)

AF:

0.00229

AC:

187

AN:

81506

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50622

Middle Eastern (MID)

AF:

0.000524

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.0000613

AC:

AN:

1092888

Other (OTH)

AF:

0.000508

AC:

AN:

59060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

109

136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000256

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.000350

AC XY:

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41542

American (AMR)

AF:

0.0000654

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.00270

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

67976

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000408

Hom.:

Bravo

AF:

0.000166

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000551

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

May 25, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Asp9Val in exon 1 of SPRED1: This variant is classified as benign because it h as been identified in 0.5% (49/9150) of Ashkenazi Jewish chromosomes by the Geno me Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs20015 7475). ACMG/AMP criteria applied: BA1.

Feb 24, 2020

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SPRED1 c.26A>T (p.Asp9Val) 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. The variant allele was found at a frequency of 0.00068 in 195612 control chromosomes, predominantly at a frequency of 0.0025 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1000 fold of the estimated maximal expected allele frequency for a pathogenic variant in SPRED1 causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrence with another pathogenic variant has been internally reported (PTPN11 c.172A>T, p.Asn58Tyr), providing supporting evidence for a benign role. Four ClinVar submitters (evaluation after 2014) cites the variant as uncertain significance (1x), likely benign (1x) and benign (2x). Based on the evidence outlined above, the variant was classified as benign.

not provided

Benign:2

Oct 11, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SPRED1: BS1

SPRED1-related disorder

Benign:1

May 16, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Legius syndrome

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

Nov 01, 2021

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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

Oct 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.17

Eigen

Benign

-0.050

Eigen_PC

Benign

0.074

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.79

M_CAP

Benign

0.059

MetaRNN

Benign

0.0047

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

-0.34

PhyloP100

5.9

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.2

REVEL

Uncertain

0.30

Sift

Uncertain

0.010

Sift4G

Benign

0.12

Polyphen

0.0020

Vest4

0.26

MVP

0.74

MPC

0.50

ClinPred

0.043

GERP RS

3.9

PromoterAI

-0.028

Neutral

(source)

Varity_R

0.18

gMVP

0.32

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over