Genetic Variant EPRS1:c.1950+126T>A (chr1-220005980-A-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.1950+126T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.811 in 542,448 control chromosomes in the GnomAD database, including 179,172 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 0.80 ( 49044 hom., cov: 30)

Exomes 𝑓: 0.81 ( 130128 hom. )

Consequence

EPRS1
NM_004446.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.337

Publications

3 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=-1.0).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.907 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPRS1	NM_004446.3 link	c.1950+126T>A		intron_variant	Intron 15 of 31	ENST00000366923.8	NP_004437.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
EPRS1	ENST00000366923.8 link	c.1950+126T>A	intron_variant	Intron 15 of 31	1	NM_004446.3	ENSP00000355890.3
EPRS1	ENST00000609181.5 link	c.1971+126T>A	intron_variant	Intron 16 of 20	1		ENSP00000477245.1
EPRS1	ENST00000477030.2 link	n.*632-620T>A	intron_variant	Intron 10 of 11	1		ENSP00000477493.1
EPRS1	ENST00000464052.5 link	n.372+126T>A	intron_variant	Intron 2 of 4	2

Frequencies

GnomAD3 genomes

AF:

0.802

AC:

121774

AN:

151820

Hom.:

49005

Cov.:

show subpopulations

Gnomad AFR

AF:

0.760

Gnomad AMI

AF:

0.775

Gnomad AMR

AF:

0.848

Gnomad ASJ

AF:

0.721

Gnomad EAS

AF:

0.929

Gnomad SAS

AF:

0.837

Gnomad FIN

AF:

0.817

Gnomad MID

AF:

0.790

Gnomad NFE

AF:

0.807

Gnomad OTH

AF:

0.796

GnomAD4 exome

AF:

0.814

AC:

318069

AN:

390510

Hom.:

130128

AF XY:

0.814

AC XY:

165552

AN XY:

203448

show subpopulations

African (AFR)

AF:

0.764

AC:

7980

AN:

10446

American (AMR)

AF:

0.867

AC:

9971

AN:

11504

Ashkenazi Jewish (ASJ)

AF:

0.732

AC:

7968

AN:

10880

East Asian (EAS)

AF:

0.920

AC:

23139

AN:

25154

South Asian (SAS)

AF:

0.827

AC:

19062

AN:

23052

European-Finnish (FIN)

AF:

0.822

AC:

25363

AN:

30840

Middle Eastern (MID)

AF:

0.753

AC:

1291

AN:

1714

European-Non Finnish (NFE)

AF:

0.807

AC:

206436

AN:

255886

Other (OTH)

AF:

0.802

AC:

16859

AN:

21034

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

2757

5514

8270

11027

13784

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2126

4252

6378

8504

10630

<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:

0.802

AC:

121867

AN:

151938

Hom.:

49044

Cov.:

AF XY:

0.804

AC XY:

59691

AN XY:

74260

show subpopulations

African (AFR)

AF:

0.761

AC:

31489

AN:

41400

American (AMR)

AF:

0.849

AC:

12964

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.721

AC:

2502

AN:

3472

East Asian (EAS)

AF:

0.929

AC:

4804

AN:

5170

South Asian (SAS)

AF:

0.836

AC:

4033

AN:

4826

European-Finnish (FIN)

AF:

0.817

AC:

8611

AN:

10540

Middle Eastern (MID)

AF:

0.777

AC:

227

AN:

292

European-Non Finnish (NFE)

AF:

0.807

AC:

54851

AN:

67940

Other (OTH)

AF:

0.796

AC:

1679

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1210

2421

3631

4842

6052

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

878

1756

2634

3512

4390

<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:

0.805

Hom.:

6118

Bravo

AF:

0.801

Asia WGS

AF:

0.888

AC:

3087

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.90

(source)

DANN

Benign

0.43

PhyloP100

-0.34

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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