dbSNP rs369362135: EDC4:p.Ala26Glu (chr16-67873338-C-A) – 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_014329.5(EDC4):c.77C>A(p.Ala26Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000154 in 1,302,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. A26G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

EDC4
NM_014329.5 missense

Scores

Clinical Significance

Not reported in ClinVar

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: 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=0.09990424).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDC4	NM_014329.5 link	c.77C>A	p.Ala26Glu	missense_variant	Exon 1 of 29	ENST00000358933.10	NP_055144.3	Q6P2E9-1
EDC4	NM_001427345.1 link	c.77C>A	p.Ala26Glu	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>A	p.Ala26Glu	missense_variant	Exon 1 of 29	1	NM_014329.5	ENSP00000351811.5	Q6P2E9-1
EDC4	ENST00000572221.5 link	n.287C>A		non_coding_transcript_exon_variant	Exon 1 of 28	2
EDC4	ENST00000536072.6 link	n.-34C>A		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000154

AC:

AN:

1302096

Hom.:

Cov.:

AF XY:

0.00000156

AC XY:

AN XY:

641058

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:

25722

American (AMR)

AF:

0.00

AC:

AN:

20026

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22296

East Asian (EAS)

AF:

0.00

AC:

AN:

28324

South Asian (SAS)

AF:

0.00

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:

0.00000192

AC:

AN:

1040184

Other (OTH)

AF:

0.00

AC:

AN:

53930

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), 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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.076

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.067

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.80

M_CAP

Benign

0.0079

MetaRNN

Benign

0.10

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

PhyloP100

3.6

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.40

REVEL

Benign

0.056

Sift

Benign

0.23

Sift4G

Benign

0.25

Polyphen

0.0020

Vest4

0.20

MutPred

0.40

Loss of sheet (P = 0.0025);

MVP

0.22

MPC

0.92

ClinPred

0.74

GERP RS

5.4

PromoterAI

0.0044

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.19

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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rs369362135

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over