Genetic Variant SPRED3:p.Gly42Trp (chr19-38390426-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001394336.1(SPRED3):c.124G>T(p.Gly42Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G42E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SPRED3
NM_001394336.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.80

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.831

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394336.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPRED3	NM_001394336.1	MANE Select	c.124G>T	p.Gly42Trp	missense	Exon 2 of 6	NP_001381265.1	Q2MJR0-1
SPRED3	NM_001042522.3		c.124G>T	p.Gly42Trp	missense	Exon 1 of 5	NP_001035987.1	Q2MJR0-1
SPRED3	NM_001394337.1		c.124G>T	p.Gly42Trp	missense	Exon 2 of 5	NP_001381266.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPRED3	ENST00000691638.1	MANE Select	c.124G>T	p.Gly42Trp	missense	Exon 2 of 6	ENSP00000510478.1	Q2MJR0-1
SPRED3	ENST00000338502.8	TSL:1	c.124G>T	p.Gly42Trp	missense	Exon 1 of 5	ENSP00000345405.4	Q2MJR0-1
SPRED3	ENST00000587564.2	TSL:1	n.128G>T		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1253948

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

612512

African (AFR)

AF:

0.00

AC:

AN:

25348

American (AMR)

AF:

0.00

AC:

AN:

16366

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18832

East Asian (EAS)

AF:

0.00

AC:

AN:

30412

South Asian (SAS)

AF:

0.00

AC:

AN:

51214

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46810

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4828

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1009418

Other (OTH)

AF:

0.00

AC:

AN:

50720

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.64

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.83

MetaSVM

Uncertain

0.30

MutationAssessor

Benign

1.3

PhyloP100

4.8

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-3.1

REVEL

Pathogenic

0.66

Sift

Benign

0.093

Sift4G

Uncertain

0.026

Polyphen

1.0

Vest4

0.71

MutPred

0.56

Loss of disorder (P = 0.005)

MVP

0.91

MPC

1.0

ClinPred

0.98

GERP RS

4.1

PromoterAI

-0.045

Neutral

(source)

Varity_R

0.19

gMVP

0.52

Mutation Taster

=72/28

polymorphism

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over