rs1057517676

chr15-74674964-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_025083.5(EDC3):c.161T>C(p.Phe54Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EDC3 NM_025083.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.76

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, EDC3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909
• PP5: Variant 15-74674964-A-G is Pathogenic according to our data. Variant chr15-74674964-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 372218.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDC3	NM_025083.5	c.161T>C	p.Phe54Ser	missense_variant	2/7	ENST00000315127.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDC3	ENST00000315127.9	c.161T>C	p.Phe54Ser	missense_variant	2/7	1	NM_025083.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual disability, autosomal recessive 50 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 02, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;D;D;D;D;D;.;.;.;.;T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.092	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	2.0	M;M;M;M;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.4	D;.;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0060	D;.;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0070	D;.;D;D;D;.;.;.;.;.;.
Polyphen		0.99	D;D;D;D;.;.;.;.;.;.;.
Vest4		0.99
MutPred		0.75		Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);
MVP		0.76
MPC		1.8
ClinPred		0.97	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.94

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

Other links and lift over

dbSNP: rs1057517676; hg19: chr15-74967305;