Genetic Variant SPRED3:p.Pro181Leu (chr19-38394761-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001394336.1(SPRED3):c.542C>T(p.Pro181Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000281 in 1,423,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P181R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

SPRED3
NM_001394336.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.98

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.34591198).

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.542C>T	p.Pro181Leu	missense	Exon 5 of 6	NP_001381265.1	Q2MJR0-1
SPRED3	NM_001042522.3		c.542C>T	p.Pro181Leu	missense	Exon 4 of 5	NP_001035987.1	Q2MJR0-1
SPRED3	NM_001394338.1		c.38C>T	p.Pro13Leu	missense	Exon 4 of 5	NP_001381267.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPRED3	ENST00000691638.1	MANE Select	c.542C>T	p.Pro181Leu	missense	Exon 5 of 6	ENSP00000510478.1	Q2MJR0-1
SPRED3	ENST00000338502.8	TSL:1	c.542C>T	p.Pro181Leu	missense	Exon 4 of 5	ENSP00000345405.4	Q2MJR0-1
SPRED3	ENST00000587013.6	TSL:5	c.674C>T	p.Pro225Leu	missense	Exon 4 of 5	ENSP00000467540.1	K7EPU5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000281

AC:

AN:

1423652

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

704996

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33128

American (AMR)

AF:

0.0000256

AC:

AN:

39036

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25350

East Asian (EAS)

AF:

0.00

AC:

AN:

38538

South Asian (SAS)

AF:

0.00

AC:

AN:

81758

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44824

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5540

European-Non Finnish (NFE)

AF:

0.00000274

AC:

AN:

1096458

Other (OTH)

AF:

0.00

AC:

AN:

59020

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.051

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0065

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.85

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.30

MetaSVM

Benign

-0.79

MutationAssessor

Benign

1.4

PhyloP100

4.0

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.4

REVEL

Benign

0.23

Sift

Benign

0.64

Sift4G

Benign

0.10

Polyphen

0.74

Vest4

0.60

MutPred

0.23

Loss of catalytic residue at P180 (P = 0.0165)

MVP

0.84

MPC

0.39

ClinPred

0.72

GERP RS

3.0

Varity_R

0.051

gMVP

0.47

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over