18-57601734-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_004539.4(NARS1):c.1565G>A(p.Arg522Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,228 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 Uncertain significance (★).
Frequency
Consequence
NM_004539.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NARS1 | ENST00000256854.10 | c.1565G>A | p.Arg522Gln | missense_variant | Exon 14 of 14 | 1 | NM_004539.4 | ENSP00000256854.4 | ||
NARS1 | ENST00000586807.5 | n.*745G>A | non_coding_transcript_exon_variant | Exon 12 of 12 | 2 | ENSP00000464988.1 | ||||
NARS1 | ENST00000589314.1 | n.645G>A | non_coding_transcript_exon_variant | Exon 3 of 3 | 5 | |||||
NARS1 | ENST00000586807.5 | n.*745G>A | 3_prime_UTR_variant | Exon 12 of 12 | 2 | ENSP00000464988.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461228Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726974
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities Uncertain:1
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with recessive neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (NEDMILG; MIM#619091). While the mechanism of dominant neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities (NEDMILEG; MIM#619092) is uncertain, toxic gain of function or dominant negative have been suggested (PMID: 32738225). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM, PMID: 32738225). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated tRNA synthetases class II (D, K and N) domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.