rs776286420
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM2BP4_ModerateBP6_Very_StrongBP7
The NM_012208.4(HARS2):c.1077T>G(p.Ala359=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000489 in 1,614,050 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 Likely benign (★★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000050 ( 0 hom. )
Consequence
HARS2
NM_012208.4 synonymous
NM_012208.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.188
Genes affected
HARS2 (HGNC:4817): (histidyl-tRNA synthetase 2, mitochondrial) Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. The protein encoded by this gene is an enzyme belonging to the class II family of aminoacyl-tRNA synthetases. Functioning in the synthesis of histidyl-transfer RNA, the enzyme plays an accessory role in the regulation of protein biosynthesis. The gene is located in a head-to-head orientation with HARS on chromosome five, where the homologous genes likely share a bidirectional promoter. Mutations in this gene are associated with the pathogenesis of Perrault syndrome, which involves ovarian dysgenesis and sensorineural hearing loss. Alternative splicing results in multiple transcript variants of this gene. [provided by RefSeq, Jul 2013]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -9 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.46).
BP6
?
Variant 5-140697286-T-G is Benign according to our data. Variant chr5-140697286-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 227424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
Synonymous conserved (PhyloP=0.188 with no splicing effect.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HARS2 | NM_012208.4 | c.1077T>G | p.Ala359= | synonymous_variant | 10/13 | ENST00000230771.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HARS2 | ENST00000230771.9 | c.1077T>G | p.Ala359= | synonymous_variant | 10/13 | 1 | NM_012208.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152166Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251472Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135916
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GnomAD4 exome AF: 0.0000499 AC: 73AN: 1461884Hom.: 0 Cov.: 34 AF XY: 0.0000523 AC XY: 38AN XY: 727244
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GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152166Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74346
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ClinVar
Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 16, 2015 | p.Ala359Ala in exon 10 of HARS2: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 1/66736 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org). - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 14, 2020 | - - |
Computational scores
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at