5-168486499-A-G
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PVS1_ModeratePS1_ModeratePP5_Very_StrongBS2_Supporting
The NM_002887.4(RARS1):āc.1A>Gā(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000103 in 1,558,408 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 (ā ā ).
Frequency
Consequence
NM_002887.4 start_lost
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152094Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000181 AC: 3AN: 165944Hom.: 0 AF XY: 0.0000229 AC XY: 2AN XY: 87510
GnomAD4 exome AF: 0.00000782 AC: 11AN: 1406314Hom.: 0 Cov.: 30 AF XY: 0.00000576 AC XY: 4AN XY: 694044
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152094Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74270
ClinVar
Submissions by phenotype
Hypomyelinating leukodystrophy 9 Pathogenic:2
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Start-lost is reinitiation of translation may occur at a downstream alternate start codon but still result in a loss or disruption of normal protein function as there have been pathogenic variants reported upstream of the alternate start codon. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 24777941). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000162083 / PMID: 24777941). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
- -
not provided Pathogenic:2
For these reasons, this variant has been classified as Pathogenic. Variants that affect the same initiator codon have been observed in individuals affected with clinical features of hypomyelinating leukodystrophy (PMID: 24777941, 27848944, 30791064, Invitae). ClinVar contains an entry for this variant (Variation ID: 162083). This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the RARS mRNA. The next in-frame methionine is located at codon 73. -
The c.1 A>G pathogenic variant in the RARS gene has previously been reported in association with hypomyelinating leukodystrophy in an individual who was compound heterozygous for another variant in RARs (Wolf et al., 2014). The pathogenic variant alters the initiator Methionine codon, and the resultant protein would be described as p.Met1? using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Met. Additionally, the c.1 A>G variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, we interpret c.1 A>G to be a pathogenic variant." -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at