Variant chr15-74655775-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_025083.5(EDC3):c.778C>T(p.Arg260Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,764 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

EDC3
NM_025083.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.73

Variant links:

Genes affected

EDC3 (HGNC:26114): (enhancer of mRNA decapping 3) This gene encodes a protein that is important in mRNA degradation. The encoded protein is a component of a decapping complex that promotes efficient removal of the monomethylguanosine (m7G) cap from mRNAs, as part of the 5' to 3' mRNA decay pathway. Mutations in this gene have been identified in human patients with an autosomal recessive form of intellectual disability. [provided by RefSeq, May 2017]

EDC3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, EDC3

BP4

Computational evidence support a benign effect (MetaRNN=0.33605945).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDC3	NM_025083.5 linkuse as main transcript	c.778C>T	p.Arg260Trp	missense_variant	4/7	ENST00000315127.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDC3	ENST00000315127.9 linkuse as main transcript	c.778C>T	p.Arg260Trp	missense_variant	4/7	1	NM_025083.5	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251380

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461764

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727162

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Intellectual disability, autosomal recessive 50

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Breda Genetics srl

Jan 22, 2021

Based on allele frequency, in-silico prediction scores and a certain overlap with the clinical phenotype, we interpreted this variant at least as of uncertain significance. The lack of one or more of the following features has discouraged further investigations: lack of a possible second hit in autosomal recessive conditions, presence of healthy controls in databases for autosomal dominant conditions, presence of unmatching cardinal clinical features in the patient or in the known gene-disease association, and/or variant type outside the known gene mutational spectrum. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.0062

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

T;T;T;T;T

Eigen

Benign

-0.039

Eigen_PC

Benign

-0.046

FATHMM_MKL

Benign

0.66

M_CAP

Benign

0.0090

MetaRNN

Benign

0.34

T;T;T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.0

L;L;L;L;.

MutationTaster

Benign

0.94

D;D;D

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.5

D;.;D;D;D

REVEL

Benign

0.19

Sift

Uncertain

0.0030

D;.;D;D;D

Sift4G

Uncertain

0.0030

D;.;D;D;.

Polyphen

1.0

D;D;D;D;.

Vest4

0.47

MutPred

0.53

Loss of disorder (P = 0.0281);Loss of disorder (P = 0.0281);Loss of disorder (P = 0.0281);Loss of disorder (P = 0.0281);.;

MVP

0.25

MPC

1.1

ClinPred

0.84

GERP RS

1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.42

gMVP

0.67

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