Genetic Variant SPRED3:p.Ser186Phe (chr19-38394776-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001394336.1(SPRED3):c.557C>T(p.Ser186Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,571,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

SPRED3
NM_001394336.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.75

Variant links:

Genes affected

SPRED3 (HGNC:31041): (sprouty related EVH1 domain containing 3) This gene encodes a protein with a C-terminal Sprouty-like cysteine-rich domain (SRY) and an N-terminal Ena/Vasodilator-stimulated phosphoprotein (VASP) homology-1 (EVH-1) domain. The encoded protein is a member of a family of proteins that negatively regulates mitogen-activated protein (MAP) kinase signaling, particularly during organogenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2012]

SPRED3 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.047413528).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPRED3	NM_001394336.1 link	c.557C>T	p.Ser186Phe	missense_variant	Exon 5 of 6	ENST00000691638.1	NP_001381265.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPRED3	ENST00000691638.1 link	c.557C>T	p.Ser186Phe	missense_variant	Exon 5 of 6		NM_001394336.1	ENSP00000510478.1		Q2MJR0-1

Frequencies

GnomAD3 genomes

AF:

0.000473

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00152

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.0000294

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000131

AC:

AN:

175888

Hom.:

AF XY:

0.0000828

AC XY:

AN XY:

96592

show subpopulations

Gnomad AFR exome

AF:

0.00162

Gnomad AMR exome

AF:

0.000258

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.0000641

AC:

AN:

1419172

Hom.:

Cov.:

AF XY:

0.0000569

AC XY:

AN XY:

702446

show subpopulations

Gnomad4 AFR exome

AF:

0.00233

Gnomad4 AMR exome

AF:

0.000208

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000102

GnomAD4 genome

AF:

0.000473

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00152

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00144

Alfa

AF:

0.000367

Hom.:

Bravo

AF:

0.000654

ESP6500AA

AF:

0.000804

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000111

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.557C>T (p.S186F) alteration is located in exon 4 (coding exon 4) of the SPRED3 gene. This alteration results from a C to T substitution at nucleotide position 557, causing the serine (S) at amino acid position 186 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.0078

.;T;T

Eigen

Benign

-0.027

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.83

T;.;T

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.047

T;T;T

MetaSVM

Benign

-0.38

MutationAssessor

Benign

1.4

.;L;L

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.3

.;.;N

REVEL

Benign

0.24

Sift

Benign

0.70

.;.;T

Sift4G

Benign

0.39

T;T;T

Polyphen

0.97

.;D;D

Vest4

0.57

MVP

0.85

MPC

0.36

ClinPred

0.077

GERP RS

3.0

Varity_R

0.091

gMVP

0.51

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