rs1474000585

Variant names:

• chr1-219981454-A-G
• rs1474000585
• NM_004446.3:c.3377T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-219981454-A-G
• chr1-219981454-A-C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_004446.3(EPRS1):​c.3377T>C​(p.Met1126Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,436,956 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: EPRS1 NM_004446.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.08
• Publications: 2 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934
• PP5: Variant 1-219981454-A-G is Pathogenic according to our data. Variant chr1-219981454-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 523137.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004446.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPRS1	NM_004446.3	MANE Select	c.3377T>C	p.Met1126Thr	missense	Exon 24 of 32	NP_004437.2	P07814

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPRS1	ENST00000366923.8	TSL:1 MANE Select	c.3377T>C	p.Met1126Thr	missense	Exon 24 of 32	ENSP00000355890.3	P07814
	EPRS1	ENST00000927912.1		c.3497T>C	p.Met1166Thr	missense	Exon 25 of 33	ENSP00000597971.1
	EPRS1	ENST00000927914.1		c.3422T>C	p.Met1141Thr	missense	Exon 25 of 33	ENSP00000597973.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1436956 Hom.: 0 Cov.: 29 AF XY: 0.00000140 AC XY: 1 AN XY: 714708

African (AFR) AF: 0.00 AC: 0 AN: 32942

American (AMR) AF: 0.00 AC: 0 AN: 42942

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25600

East Asian (EAS) AF: 0.00 AC: 0 AN: 39420

South Asian (SAS) AF: 0.00 AC: 0 AN: 81286

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5668

European-Non Finnish (NFE) AF: 9.11e-7 AC: 1 AN: 1097546

Other (OTH) AF: 0.00 AC: 0 AN: 59266

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Leukodystrophy, hypomyelinating, 15 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		9.1
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.79		Gain of phosphorylation at M1126 (P = 0.0964)
MVP		0.95
MPC		0.72
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.90
gMVP		0.92
Mutation Taster		=10/90	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1474000585; hg19: chr1-220154796;