1-220024283-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004446.3(EPRS1):c.924C>A(p.Asp308Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.825 in 1,594,018 control chromosomes in the GnomAD database, including 544,784 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.86 ( 57253 hom., cov: 34)

Exomes 𝑓: 0.82 ( 487531 hom. )

Consequence

EPRS1
NM_004446.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.344

Publications

39 publications found

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 Gene-Disease associations (from GenCC):

leukodystrophy, hypomyelinating, 15
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

EPRS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.2932273E-6).

BP6

Variant 1-220024283-G-T is Benign according to our data. Variant chr1-220024283-G-T is described in ClinVar as Benign. ClinVar VariationId is 1166609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.959 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPRS1	NM_004446.3 link	c.924C>A	p.Asp308Glu	missense_variant	Exon 8 of 32	ENST00000366923.8	NP_004437.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
EPRS1	ENST00000366923.8 link	c.924C>A	p.Asp308Glu	missense_variant	Exon 8 of 32	1	NM_004446.3	ENSP00000355890.3
EPRS1	ENST00000609181.5 link	c.924C>A	p.Asp308Glu	missense_variant	Exon 8 of 21	1		ENSP00000477245.1
EPRS1	ENST00000477030.2 link	n.*244C>A		non_coding_transcript_exon_variant	Exon 7 of 12	1		ENSP00000477493.1
EPRS1	ENST00000477030.2 link	n.*244C>A		3_prime_UTR_variant	Exon 7 of 12	1		ENSP00000477493.1

Frequencies

GnomAD3 genomes

AF:

0.864

AC:

131431

AN:

152130

Hom.:

57200

Cov.:

show subpopulations

Gnomad AFR

AF:

0.967

Gnomad AMI

AF:

0.776

Gnomad AMR

AF:

0.874

Gnomad ASJ

AF:

0.748

Gnomad EAS

AF:

0.932

Gnomad SAS

AF:

0.849

Gnomad FIN

AF:

0.817

Gnomad MID

AF:

0.813

Gnomad NFE

AF:

0.810

Gnomad OTH

AF:

0.847

GnomAD2 exomes

AF:

0.842

AC:

197162

AN:

234180

AF XY:

0.835

show subpopulations

Gnomad AFR exome

AF:

0.970

Gnomad AMR exome

AF:

0.909

Gnomad ASJ exome

AF:

0.742

Gnomad EAS exome

AF:

0.935

Gnomad FIN exome

AF:

0.817

Gnomad NFE exome

AF:

0.805

Gnomad OTH exome

AF:

0.830

GnomAD4 exome

AF:

0.821

AC:

1183923

AN:

1441770

Hom.:

487531

Cov.:

AF XY:

0.820

AC XY:

588200

AN XY:

717234

show subpopulations

African (AFR)

AF:

0.974

AC:

31423

AN:

32256

American (AMR)

AF:

0.904

AC:

35209

AN:

38946

Ashkenazi Jewish (ASJ)

AF:

0.751

AC:

18870

AN:

25138

East Asian (EAS)

AF:

0.926

AC:

36605

AN:

39546

South Asian (SAS)

AF:

0.838

AC:

68848

AN:

82162

European-Finnish (FIN)

AF:

0.822

AC:

43659

AN:

53106

Middle Eastern (MID)

AF:

0.797

AC:

4515

AN:

5662

European-Non Finnish (NFE)

AF:

0.810

AC:

895628

AN:

1105388

Other (OTH)

AF:

0.825

AC:

49166

AN:

59566

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

9240

18480

27721

36961

46201

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20834

41668

62502

83336

104170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.864

AC:

131541

AN:

152248

Hom.:

57253

Cov.:

AF XY:

0.864

AC XY:

64285

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.967

AC:

40196

AN:

41580

American (AMR)

AF:

0.874

AC:

13363

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.748

AC:

2598

AN:

3472

East Asian (EAS)

AF:

0.932

AC:

4823

AN:

5174

South Asian (SAS)

AF:

0.847

AC:

4084

AN:

4824

European-Finnish (FIN)

AF:

0.817

AC:

8649

AN:

10582

Middle Eastern (MID)

AF:

0.803

AC:

236

AN:

294

European-Non Finnish (NFE)

AF:

0.810

AC:

55094

AN:

68006

Other (OTH)

AF:

0.848

AC:

1790

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

909

1819

2728

3638

4547

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

894

1788

2682

3576

4470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.825

Hom.:

174874

Bravo

AF:

0.873

TwinsUK

AF:

0.816

AC:

3024

ALSPAC

AF:

0.814

AC:

3137

ESP6500AA

AF:

0.957

AC:

4216

ESP6500EA

AF:

0.809

AC:

6957

ExAC

AF:

0.844

AC:

102427

Asia WGS

AF:

0.911

AC:

3167

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Leukodystrophy, hypomyelinating, 15

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.24

(source)

DANN

Benign

0.21

DEOGEN2

Benign

0.22

T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.33

T;T

MetaRNN

Benign

0.0000013

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.69

N;.

PhyloP100

0.34

PrimateAI

Uncertain

0.49

PROVEAN

Benign

1.2

N;.

REVEL

Benign

0.21

Sift

Benign

1.0

T;.

Sift4G

Benign

1.0

T;.

Vest4

0.043

ClinPred

0.00069

GERP RS

-1.6

Varity_R

0.057

gMVP

0.22

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over