chr5-140693619-T-A
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4
The NM_012208.4(HARS2):c.137T>A(p.Leu46Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).
Frequency
Genomes: not found (cov: 32)
Consequence
HARS2
NM_012208.4 missense
NM_012208.4 missense
Scores
2
3
13
Clinical Significance
Conservation
PhyloP100: 3.26
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 Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-140693619-T-A is Pathogenic according to our data. Variant chr5-140693619-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 633638.Status of the report is no_assertion_criteria_provided, 0 stars.
BP4
Computational evidence support a benign effect (MetaRNN=0.33348727). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HARS2 | NM_012208.4 | c.137T>A | p.Leu46Gln | missense_variant | 2/13 | ENST00000230771.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HARS2 | ENST00000230771.9 | c.137T>A | p.Leu46Gln | missense_variant | 2/13 | 1 | NM_012208.4 | A1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Perrault syndrome 2 Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | May 20, 2019 | Variant detected as compound heterozygous, together with c.259C>T in a female with perrault syndrome - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;.;.;.;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;.;.;.;.;M;M
MutationTaster
Benign
D;D;D;D;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;.;.;.;.;.;.
REVEL
Benign
Sift
Benign
D;.;.;.;.;.;.
Sift4G
Benign
T;.;.;.;.;.;.
Polyphen
D;.;.;.;.;D;D
Vest4
MutPred
Gain of disorder (P = 0.0165);.;Gain of disorder (P = 0.0165);Gain of disorder (P = 0.0165);.;Gain of disorder (P = 0.0165);Gain of disorder (P = 0.0165);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at