Genetic Variant EDC4:p.Ser6Ile (chr16-67873278-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_014329.5(EDC4):c.17G>T(p.Ser6Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

EDC4
NM_014329.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.12

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: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a modified_residue Phosphoserine (size 0) in uniprot entity EDC4_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33254015).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDC4	NM_014329.5 link	c.17G>T	p.Ser6Ile	missense_variant	Exon 1 of 29	ENST00000358933.10	NP_055144.3	Q6P2E9-1
EDC4	NM_001427345.1 link	c.17G>T	p.Ser6Ile	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.17G>T	p.Ser6Ile	missense_variant	Exon 1 of 29	1	NM_014329.5	ENSP00000351811.5	Q6P2E9-1
EDC4	ENST00000572221.5 link	n.227G>T		non_coding_transcript_exon_variant	Exon 1 of 28	2
EDC4	ENST00000536072.6 link	n.-94G>T		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1320390

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

650082

African (AFR)

AF:

0.00

AC:

AN:

26570

American (AMR)

AF:

0.00

AC:

AN:

24714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23174

East Asian (EAS)

AF:

0.00

AC:

AN:

28630

South Asian (SAS)

AF:

0.00

AC:

AN:

72480

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37038

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4810

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1048320

Other (OTH)

AF:

0.00

AC:

AN:

54654

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 11, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.17G>T (p.S6I) alteration is located in exon 1 (coding exon 1) of the EDC4 gene. This alteration results from a G to T substitution at nucleotide position 17, causing the serine (S) at amino acid position 6 to be replaced by an isoleucine (I). 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

Uncertain

0.42

BayesDel_addAF

Uncertain

0.058

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.082

MetaRNN

Benign

0.33

MetaSVM

Benign

-0.54

MutationAssessor

Benign

1.8

PhyloP100

5.1

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.35

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

0.99

Vest4

0.24

MutPred

0.47

Loss of disorder (P = 0.0149);

MVP

0.33

MPC

1.9

ClinPred

0.98

GERP RS

5.4

PromoterAI

0.081

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.77

gMVP

0.39

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over