chr15-74655735-G-A

Position:

• chr15-74655735-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_025083.5(EDC3):​c.818C>T​(p.Thr273Met) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000756 in 1,454,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T273T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: EDC3 NM_025083.5 missense, splice_region
• Scores: Splicing: ADA: 0.8315
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

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 5 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, 0.868

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDC3	NM_025083.5	c.818C>T	p.Thr273Met	missense_variant, splice_region_variant	4/7	ENST00000315127.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDC3	ENST00000315127.9	c.818C>T	p.Thr273Met	missense_variant, splice_region_variant	4/7	1	NM_025083.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249872 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135054

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000756 AC: 11 AN: 1454802 Hom.: 0 Cov.: 32 AF XY: 0.00000415 AC XY: 3 AN XY: 722290

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000813

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 27, 2023

Variant summary: EDC3 c.818C>T (p.Thr273Met) results in a non-conservative amino acid change located in the FDF domain (IPR019050) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. In addition, this variant disrupts the third-to-last nucleotide of exon 4, and therefore can affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 249872 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.818C>T in individuals affected with Intellectual Disability, Autosomal Recessive 50 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.43	T;T;T;T;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D
MetaSVM	Uncertain	-0.073	T
MutationAssessor	Uncertain	2.8	M;M;M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.6	D;.;D;D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D;.;D;D;D
Sift4G	Uncertain	0.0030	D;.;D;D;.
Polyphen		1.0	D;D;D;D;.
Vest4		0.82
MVP		0.62
MPC		1.4
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.75
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.83
dbscSNV1_RF	Benign	0.54
SpliceAI score (max)		0.020		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: rs892679695; hg19: chr15-74948076;