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rs898824971

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_004446.3(EPRS1):c.3478C>T(p.Pro1160Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 779,694 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 Pathogenic (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000064 ( 0 hom. )

Consequence

EPRS1
NM_004446.3 missense

Scores

14
4
1

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.74
Variant links:
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 Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.898
PP5
Variant 1-219980833-G-A is Pathogenic according to our data. Variant chr1-219980833-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 523135.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
EPRS1NM_004446.3 linkuse as main transcriptc.3478C>T p.Pro1160Ser missense_variant 25/32 ENST00000366923.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
EPRS1ENST00000366923.8 linkuse as main transcriptc.3478C>T p.Pro1160Ser missense_variant 25/321 NM_004446.3 P1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152154
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000637
AC:
4
AN:
627540
Hom.:
0
Cov.:
30
AF XY:
0.00000585
AC XY:
2
AN XY:
341780
show subpopulations
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000114
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152154
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74296
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000564
Hom.:
0
Bravo
AF:
0.0000151
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000595

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Leukodystrophy, hypomyelinating, 15 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 03, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.93
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Pathogenic
0.14
Cadd
Pathogenic
31
Dann
Pathogenic
1.0
DEOGEN2
Uncertain
0.76
D
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
1.0
D
M_CAP
Uncertain
0.11
D
MetaRNN
Pathogenic
0.90
D
MetaSVM
Uncertain
0.56
D
MutationAssessor
Pathogenic
4.2
H
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.83
D
PROVEAN
Pathogenic
-7.2
D
REVEL
Uncertain
0.62
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.79
MVP
0.94
MPC
0.67
ClinPred
1.0
D
GERP RS
6.1
Varity_R
0.92
gMVP
0.90

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs898824971; hg19: chr1-220154175; COSMIC: COSV65098530; COSMIC: COSV65098530; API