chr1-219968901-G-T
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate
The NM_004446.3(EPRS1):c.4444C>A(p.Pro1482Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
EPRS1
NM_004446.3 missense
NM_004446.3 missense
Scores
10
6
3
Clinical Significance
Conservation
PhyloP100: 8.15
Genes affected
EPRS1 (HGNC:3418): (glutamyl-prolyl-tRNA synthetase 1) Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. The protein encoded by this gene is a multifunctional aminoacyl-tRNA synthetase that catalyzes the aminoacylation of glutamic acid and proline tRNA species. Alternative splicing has been observed for this gene, but the full-length nature and biological validity of the variant have not been determined. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.969
PP5
?
Variant 1-219968901-G-T is Pathogenic according to our data. Variant chr1-219968901-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3069175.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EPRS1 | NM_004446.3 | c.4444C>A | p.Pro1482Thr | missense_variant | 32/32 | ENST00000366923.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EPRS1 | ENST00000366923.8 | c.4444C>A | p.Pro1482Thr | missense_variant | 32/32 | 1 | NM_004446.3 | P1 | |
EPRS1 | ENST00000468487.1 | n.246C>A | non_coding_transcript_exon_variant | 2/2 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461754Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727196
GnomAD4 exome
AF:
AC:
6
AN:
1461754
Hom.:
Cov.:
32
AF XY:
AC XY:
4
AN XY:
727196
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Leukodystrophy, hypomyelinating, 15 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing;in vivo | Costain lab, The Hospital for Sick Children | Jan 01, 2024 | PS3, PM2. Please see publication by Kahn et al., An EPRS1 missense variant in siblings with hypomyelinating leukodystrophy 15 uncovers an etiologic principle of altered accessibility of variant-distal mRNA m6A sites, Nature Communications [pending publication at time of ClinVar entry] - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Uncertain
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of catalytic residue at P1482 (P = 0.0565);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at