chr1-219982801-GG-AA

Variant names:

• chr1-219982801-GG-AA
• NM_004446.3:c.3343_3344delCCinsTT
• EPRS1 p.Pro1115Leu

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM5 PP3

The NM_004446.3(EPRS1):​c.3343_3344delCCinsTT​(p.Pro1115Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1115R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EPRS1 NM_004446.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.74
• Publications: 0 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 3 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-219982801-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 523133.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.3343_3344delCCinsTT	p.Pro1115Leu	missense	N/A	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.3343_3344delCCinsTT	p.Pro1115Leu	missense	N/A	ENSP00000355890.3	P07814
	EPRS1	ENST00000927912.1		c.3463_3464delCCinsTT	p.Pro1155Leu	missense	N/A	ENSP00000597971.1
	EPRS1	ENST00000927914.1		c.3388_3389delCCinsTT	p.Pro1130Leu	missense	N/A	ENSP00000597973.1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.7

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-220156143;