rs938453967
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_002109.6(HARS1):c.729+3A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000188 in 1,595,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
HARS1
NM_002109.6 splice_donor_region, intron
NM_002109.6 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.9961
2
Clinical Significance
Conservation
PhyloP100: 0.784
Genes affected
HARS1 (HGNC:4816): (histidyl-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 cytoplasmic enzyme which belongs to the class II family of aminoacyl-tRNA synthetases. The enzyme is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. The gene is located in a head-to-head orientation with HARSL on chromosome five, where the homologous genes share a bidirectional promoter. The gene product is a frequent target of autoantibodies in the human autoimmune disease polymyositis/dermatomyositis. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HARS1 | NM_002109.6 | c.729+3A>G | splice_donor_region_variant, intron_variant | ENST00000504156.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HARS1 | ENST00000504156.7 | c.729+3A>G | splice_donor_region_variant, intron_variant | 1 | NM_002109.6 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000661 AC: 1AN: 151310Hom.: 0 Cov.: 31
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GnomAD4 exome AF: 0.00000138 AC: 2AN: 1444526Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0AN XY: 719966
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GnomAD4 genome ? AF: 0.00000661 AC: 1AN: 151310Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 73810
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Usher syndrome type 3B Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 12, 2023 | This sequence change falls in intron 7 of the HARS gene. It does not directly change the encoded amino acid sequence of the HARS protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with HARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 472994). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -9
Find out detailed SpliceAI scores and Pangolin per-transcript scores at