15-38253211-A-T

Position:

chr15-38253211-A-T

Variant summary

Our verdict is Benign. Variant got -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. 12/21 in silico tools predict 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. D9E) has been classified as Likely benign.

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

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 -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 39 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPRED1	NM_152594.3 linkuse as main transcript	c.26A>T	p.Asp9Val	missense_variant	1/7	ENST00000299084.9	NP_689807.1	Q7Z699
SPRED1	XM_005254202.4 linkuse as main transcript	c.26A>T	p.Asp9Val	missense_variant	1/8		XP_005254259.1
SPRED1	XM_047432199.1 linkuse as main transcript	c.-138A>T		5_prime_UTR_variant	1/9		XP_047288155.1
SPRED1	XM_047432200.1 linkuse as main transcript	c.-102A>T		5_prime_UTR_variant	1/8		XP_047288156.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SPRED1	ENST00000299084.9 linkuse as main transcript	c.26A>T	p.Asp9Val	missense_variant	1/7	1	NM_152594.3	ENSP00000299084.4	Q7Z699
SPRED1	ENST00000561317 linkuse as main transcript	c.-102A>T		5_prime_UTR_variant	1/6	4		ENSP00000453680.1	H0YMN8
SPRED1	ENST00000561205.1 linkuse as main transcript	n.364A>T		non_coding_transcript_exon_variant	1/5	5

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

GnomAD3 exomes

AF:

0.000680

AC:

133

AN:

195612

Hom.:

AF XY:

0.000786

AC XY:

AN XY:

104268

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 SAS exome

AF:

0.00255

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

Gnomad4 AFR exome

AF:

0.0000306

Gnomad4 AMR exome

AF:

0.000273

Gnomad4 ASJ exome

AF:

0.00529

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00229

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000613

Gnomad4 OTH exome

AF:

0.000508

GnomAD4 genome

AF:

0.000256

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.000350

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00270

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.000473

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

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 25, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 24, 2020	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

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2019	This variant is associated with the following publications: (PMID: 26635368, 22753041, 31401120) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	SPRED1: BS1 -

SPRED1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 16, 2022

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). -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 01, 2021

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. -

Legius syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Noonan syndrome and Noonan-related syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

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

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

Varity_R

0.18

gMVP

0.32

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

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