rs2647449

Variant names:

• chr1-220003621-A-G
• rs2647449
• NM_004446.3:c.2063+1627T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004446.3(EPRS1):​c.2063+1627T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.807 in 152,152 control chromosomes in the GnomAD database, including 49,732 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 0.81 (49732 hom., cov: 33)
• Consequence: EPRS1 NM_004446.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.21
• Publications: 3 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• 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	c.2063+1627T>C		intron_variant	Intron 16 of 31	ENST00000366923.8	NP_004437.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPRS1	ENST00000366923.8	c.2063+1627T>C		intron_variant	Intron 16 of 31	1	NM_004446.3	ENSP00000355890.3
EPRS1	ENST00000609181.5	c.2084+1627T>C		intron_variant	Intron 17 of 20	1		ENSP00000477245.1
EPRS1	ENST00000477030.2	n.*744+1627T>C		intron_variant	Intron 11 of 11	1		ENSP00000477493.1
EPRS1	ENST00000464052.5	n.485+1627T>C		intron_variant	Intron 3 of 4	2

Frequencies

GnomAD3 genomes AF: 0.807 AC: 122760 AN: 152034 Hom.: 49693 Cov.: 33

Gnomad AFR AF: 0.780

Gnomad AMI AF: 0.778

Gnomad AMR AF: 0.849

Gnomad ASJ AF: 0.721

Gnomad EAS AF: 0.929

Gnomad SAS AF: 0.837

Gnomad FIN AF: 0.818

Gnomad MID AF: 0.788

Gnomad NFE AF: 0.807

Gnomad OTH AF: 0.798

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.807 AC: 122852 AN: 152152 Hom.: 49732 Cov.: 33 AF XY: 0.809 AC XY: 60137 AN XY: 74354

African (AFR) AF: 0.780 AC: 32361 AN: 41496

American (AMR) AF: 0.849 AC: 12990 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.721 AC: 2501 AN: 3468

East Asian (EAS) AF: 0.929 AC: 4807 AN: 5174

South Asian (SAS) AF: 0.835 AC: 4027 AN: 4820

European-Finnish (FIN) AF: 0.818 AC: 8642 AN: 10570

Middle Eastern (MID) AF: 0.776 AC: 228 AN: 294

European-Non Finnish (NFE) AF: 0.807 AC: 54899 AN: 68014

Other (OTH) AF: 0.799 AC: 1691 AN: 2116

Alfa AF: 0.815 Hom.: 8551

Bravo AF: 0.807

Asia WGS AF: 0.890 AC: 3094 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	2.2
DANN	Benign	0.66
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2647449; hg19: chr1-220176963;