15-74656040-CT-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_025083.5(EDC3):c.512del(p.Gln171ArgfsTer9) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: EDC3 NM_025083.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.46

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-74656040-CT-C is Pathogenic according to our data. Variant chr15-74656040-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 3068515.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDC3	NM_025083.5	c.512del	p.Gln171ArgfsTer9	frameshift_variant	4/7	ENST00000315127.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDC3	ENST00000315127.9	c.512del	p.Gln171ArgfsTer9	frameshift_variant	4/7	1	NM_025083.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal recessive 50 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute for Human Genetics and Genomic Medicine, Uniklinik RWTH Aachen

Apr 10, 2024

The detected variant has not yet been reported in databases (dbSNP, ClinVar, gnomAD) or in the literature. Bioinformatics tools (SIFT(v6.2.0), MutationTaster (v2021), PolyPhen-2) predict a damaging effect of the variant. ACMG criteria are PVS1, PM2, PM3. The variants meets the criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-74948381;