rs781549967
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PVS1PM2PP5BS1_Supporting
The NM_012208.4(HARS2):c.489dup(p.Ile164HisfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000514 in 1,614,214 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000053 ( 0 hom. )
Consequence
HARS2
NM_012208.4 frameshift
NM_012208.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.16
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 5-140695595-A-AC is Pathogenic according to our data. Variant chr5-140695595-A-AC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225386.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.
BS1
?
Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000534 (78/1461894) while in subpopulation EAS AF= 0.00194 (77/39700). AF 95% confidence interval is 0.00159. There are 0 homozygotes in gnomad4_exome. There are 46 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HARS2 | NM_012208.4 | c.489dup | p.Ile164HisfsTer7 | frameshift_variant | 5/13 | ENST00000230771.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HARS2 | ENST00000230771.9 | c.489dup | p.Ile164HisfsTer7 | frameshift_variant | 5/13 | 1 | NM_012208.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152202Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
5
AN:
152202
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000875 AC: 22AN: 251492Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135922
GnomAD3 exomes
AF:
AC:
22
AN:
251492
Hom.:
AF XY:
AC XY:
14
AN XY:
135922
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000534 AC: 78AN: 1461894Hom.: 0 Cov.: 33 AF XY: 0.0000633 AC XY: 46AN XY: 727248
GnomAD4 exome
AF:
AC:
78
AN:
1461894
Hom.:
Cov.:
33
AF XY:
AC XY:
46
AN XY:
727248
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152320Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74478
GnomAD4 genome
?
AF:
AC:
5
AN:
152320
Hom.:
Cov.:
32
AF XY:
AC XY:
4
AN XY:
74478
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
Asia WGS
AF:
AC:
4
AN:
3478
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 31, 2023 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 05, 2022 | This sequence change creates a premature translational stop signal (p.Ile164Hisfs*7) in the HARS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HARS2 are known to be pathogenic (PMID: 31827252). This variant is present in population databases (rs781549967, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with HARS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 225386). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Perrault syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | reference population | Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Mar 18, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 38
Find out detailed SpliceAI scores and Pangolin per-transcript scores at