Genetic Variant EDC4:p.Ala26Gly (chr16-67873338-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014329.5(EDC4):c.77C>G(p.Ala26Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000894 in 1,454,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000084 ( 0 hom. )

Consequence

EDC4
NM_014329.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.64

Publications

0 publications found

Variant links:

Genes affected

EDC4 (HGNC:17157): (enhancer of mRNA decapping 4) Predicted to be involved in deadenylation-independent decapping of nuclear-transcribed mRNA. Located in P-body and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

EDC4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.047341257).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDC4	NM_014329.5 link	c.77C>G	p.Ala26Gly	missense_variant	Exon 1 of 29	ENST00000358933.10	NP_055144.3	Q6P2E9-1
EDC4	NM_001427345.1 link	c.77C>G	p.Ala26Gly	missense_variant	Exon 1 of 28		NP_001414274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EDC4	ENST00000358933.10 link	c.77C>G	p.Ala26Gly	missense_variant	Exon 1 of 29	1	NM_014329.5	ENSP00000351811.5	Q6P2E9-1
EDC4	ENST00000572221.5 link	n.287C>G		non_coding_transcript_exon_variant	Exon 1 of 28	2
EDC4	ENST00000536072.6 link	n.-34C>G		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152018

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000479

GnomAD4 exome

AF:

0.00000845

AC:

AN:

1302096

Hom.:

Cov.:

AF XY:

0.00000780

AC XY:

AN XY:

641058

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25722

American (AMR)

AF:

0.00

AC:

AN:

20026

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22296

East Asian (EAS)

AF:

0.000106

AC:

AN:

28324

South Asian (SAS)

AF:

0.0000571

AC:

AN:

70042

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36180

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5392

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1040184

Other (OTH)

AF:

0.0000742

AC:

AN:

53930

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41482

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000194

AC:

AN:

5150

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67998

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 31, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.77C>G (p.A26G) alteration is located in exon 1 (coding exon 1) of the EDC4 gene. This alteration results from a C to G substitution at nucleotide position 77, causing the alanine (A) at amino acid position 26 to be replaced by a glycine (G). 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

0.084

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.069

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.81

M_CAP

Benign

0.0071

MetaRNN

Benign

0.047

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.065

PhyloP100

3.6

PrimateAI

Benign

0.38

PROVEAN

Benign

0.32

REVEL

Benign

0.061

Sift

Benign

0.34

Sift4G

Benign

0.73

Polyphen

0.0

Vest4

0.10

MutPred

0.39

Loss of sheet (P = 0.0025);

MVP

0.19

MPC

0.80

ClinPred

0.71

GERP RS

5.4

PromoterAI

-0.075

Neutral

(source)

Varity_R

0.097

gMVP

0.12

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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16-67873338-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over