chr15-38351273-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_152594.3(SPRED1):c.944C>T(p.Pro315Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P315S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

SPRED1
NM_152594.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 7.76

Publications

2 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.22674695).

BP6

Variant 15-38351273-C-T is Benign according to our data. Variant chr15-38351273-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 468801.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000256 (39/152234) while in subpopulation AFR AF = 0.000939 (39/41542). AF 95% confidence interval is 0.000706. There are 0 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPRED1	NM_152594.3	MANE Select	c.944C>T	p.Pro315Leu	missense	Exon 7 of 7	NP_689807.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SPRED1	ENST00000299084.9	TSL:1 MANE Select	c.944C>T	p.Pro315Leu	missense	Exon 7 of 7	ENSP00000299084.4
SPRED1	ENST00000881380.1		c.980C>T	p.Pro327Leu	missense	Exon 8 of 8	ENSP00000551439.1
SPRED1	ENST00000951939.1		c.965C>T	p.Pro322Leu	missense	Exon 8 of 8	ENSP00000621998.1

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000942

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000876

AC:

AN:

251148

AF XY:

0.0000589

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461826

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.000538

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111986

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

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:

152234

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.000939

AC:

AN:

41542

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

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:

0.0000905

Hom.:

Bravo

AF:

0.000234

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000132

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Legius syndrome (2)

Cardiovascular phenotype (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.070

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.050

MetaRNN

Benign

0.23

MetaSVM

Uncertain

0.69

MutationAssessor

Uncertain

2.9

PhyloP100

7.8

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-6.5

REVEL

Uncertain

0.59

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.48

MVP

0.72

MPC

1.1

ClinPred

0.38

GERP RS

5.7

Varity_R

0.47

gMVP

0.68

Mutation Taster

=42/58

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

Computational scores

Splicing

Publications

Other links and lift over