Genetic Variant EPRS1:c.*125G>A (chr1-219968681-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004446.3(EPRS1):c.*125G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.473 in 879,570 control chromosomes in the GnomAD database, including 99,194 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.46 ( 16212 hom., cov: 33)

Exomes 𝑓: 0.48 ( 82982 hom. )

Consequence

EPRS1
NM_004446.3 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0490

Publications

11 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.507 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPRS1	NM_004446.3 link	c.*125G>A		3_prime_UTR_variant	Exon 32 of 32	ENST00000366923.8	NP_004437.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPRS1	ENST00000366923.8 link	c.*125G>A		3_prime_UTR_variant	Exon 32 of 32	1	NM_004446.3	ENSP00000355890.3
EPRS1	ENST00000468487.1 link	n.*8G>A		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.461

AC:

69960

AN:

151910

Hom.:

16206

Cov.:

show subpopulations

Gnomad AFR

AF:

0.425

Gnomad AMI

AF:

0.441

Gnomad AMR

AF:

0.412

Gnomad ASJ

AF:

0.482

Gnomad EAS

AF:

0.522

Gnomad SAS

AF:

0.525

Gnomad FIN

AF:

0.548

Gnomad MID

AF:

0.424

Gnomad NFE

AF:

0.469

Gnomad OTH

AF:

0.467

GnomAD4 exome

AF:

0.476

AC:

345987

AN:

727544

Hom.:

82982

Cov.:

AF XY:

0.476

AC XY:

177001

AN XY:

372080

show subpopulations

African (AFR)

AF:

0.416

AC:

7477

AN:

17966

American (AMR)

AF:

0.385

AC:

8802

AN:

22872

Ashkenazi Jewish (ASJ)

AF:

0.482

AC:

7687

AN:

15932

East Asian (EAS)

AF:

0.480

AC:

16273

AN:

33900

South Asian (SAS)

AF:

0.523

AC:

26122

AN:

49994

European-Finnish (FIN)

AF:

0.534

AC:

24743

AN:

46328

Middle Eastern (MID)

AF:

0.393

AC:

1257

AN:

3196

European-Non Finnish (NFE)

AF:

0.472

AC:

237109

AN:

502218

Other (OTH)

AF:

0.470

AC:

16517

AN:

35138

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

8830

17660

26491

35321

44151

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5014

10028

15042

20056

25070

<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:

0.460

AC:

70003

AN:

152026

Hom.:

16212

Cov.:

AF XY:

0.464

AC XY:

34502

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.426

AC:

17643

AN:

41462

American (AMR)

AF:

0.412

AC:

6281

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.482

AC:

1672

AN:

3468

East Asian (EAS)

AF:

0.521

AC:

2693

AN:

5166

South Asian (SAS)

AF:

0.524

AC:

2530

AN:

4826

European-Finnish (FIN)

AF:

0.548

AC:

5790

AN:

10564

Middle Eastern (MID)

AF:

0.412

AC:

121

AN:

294

European-Non Finnish (NFE)

AF:

0.469

AC:

31894

AN:

67970

Other (OTH)

AF:

0.464

AC:

979

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

2003

4005

6008

8010

10013

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

656

1312

1968

2624

3280

<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:

0.454

Hom.:

4394

Bravo

AF:

0.447

Asia WGS

AF:

0.549

AC:

1911

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

4.8

(source)

DANN

Benign

0.37

PhyloP100

0.049

Mutation Taster

=100/0

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

Computational scores

Splicing

Publications

Other links and lift over