Genetic Variant NM_001394336.1:c.562G>T (chr19-38394781-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001394336.1(SPRED3):c.562G>T(p.Ala188Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000708 in 1,412,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. A188T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

SPRED3
NM_001394336.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.756

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10006887).

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.562G>T	p.Ala188Ser	missense	Exon 5 of 6	NP_001381265.1	Q2MJR0-1
SPRED3	NM_001042522.3		c.562G>T	p.Ala188Ser	missense	Exon 4 of 5	NP_001035987.1	Q2MJR0-1
SPRED3	NM_001394338.1		c.58G>T	p.Ala20Ser	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.562G>T	p.Ala188Ser	missense	Exon 5 of 6	ENSP00000510478.1	Q2MJR0-1
SPRED3	ENST00000338502.8	TSL:1	c.562G>T	p.Ala188Ser	missense	Exon 4 of 5	ENSP00000345405.4	Q2MJR0-1
SPRED3	ENST00000587013.6	TSL:5	c.694G>T	p.Ala232Ser	missense	Exon 4 of 5	ENSP00000467540.1	K7EPU5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000592

AC:

AN:

169024

AF XY:

0.0000108

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000731

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.08e-7

AC:

AN:

1412594

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

698534

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32944

American (AMR)

AF:

0.00

AC:

AN:

37754

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25096

East Asian (EAS)

AF:

0.00

AC:

AN:

38282

South Asian (SAS)

AF:

0.00

AC:

AN:

80890

European-Finnish (FIN)

AF:

0.0000233

AC:

AN:

42956

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5350

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1090718

Other (OTH)

AF:

0.00

AC:

AN:

58604

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.090

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.0022

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.75

M_CAP

Benign

0.052

MetaRNN

Benign

0.10

MetaSVM

Benign

-0.76

MutationAssessor

Benign

1.6

PhyloP100

0.76

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.070

REVEL

Benign

0.15

Sift

Benign

0.82

Sift4G

Benign

0.81

Polyphen

0.22

Vest4

0.34

MutPred

0.25

Gain of relative solvent accessibility (P = 0.0023)

MVP

0.63

MPC

0.26

ClinPred

0.056

GERP RS

-0.38

Varity_R

0.071

gMVP

0.34

Mutation Taster

=91/9

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over