chr1-219972083-G-C

Position:

chr1-219972083-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP3BS1_Supporting

The NM_004446.3(EPRS1):c.4309C>G(p.Leu1437Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000577 in 1,593,076 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

EPRS1
NM_004446.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.27

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]

EPRS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.805

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000593 (9/151700) while in subpopulation NFE AF= 0.000132 (9/67954). AF 95% confidence interval is 0.0000681. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPRS1	NM_004446.3 linkuse as main transcript	c.4309C>G	p.Leu1437Val	missense_variant	30/32	ENST00000366923.8	NP_004437.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPRS1	ENST00000366923.8 linkuse as main transcript	c.4309C>G	p.Leu1437Val	missense_variant	30/32	1	NM_004446.3	ENSP00000355890	P1

Frequencies

GnomAD3 genomes

AF:

0.0000593

AC:

AN:

151700

Hom.:

Cov.:

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000712

AC:

AN:

238676

Hom.:

AF XY:

0.0000541

AC XY:

AN XY:

129294

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000103

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000466

Gnomad NFE exome

AF:

0.000136

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000576

AC:

AN:

1441376

Hom.:

Cov.:

AF XY:

0.0000711

AC XY:

AN XY:

717290

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000389

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000376

Gnomad4 NFE exome

AF:

0.0000699

Gnomad4 OTH exome

AF:

0.0000504

GnomAD4 genome

AF:

0.0000593

AC:

AN:

151700

Hom.:

Cov.:

AF XY:

0.0000540

AC XY:

AN XY:

74036

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:

0.000132

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 16, 2022	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1437 of the EPRS protein (p.Leu1437Val). This variant is present in population databases (rs148671123, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with EPRS-related conditions. ClinVar contains an entry for this variant (Variation ID: 872622). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.026

MetaRNN

Pathogenic

0.81

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

0.94

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.27

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.81

MVP

0.70

MPC

0.61

ClinPred

0.51

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.82

gMVP

0.68

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over