chr5-140691748-C-A
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_012208.4(HARS2):c.100C>A(p.Gln34Lys) 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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
HARS2
NM_012208.4 missense
NM_012208.4 missense
Scores
18
Clinical Significance
Conservation
PhyloP100: 1.17
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 Likely_benign. Variant got -2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.05889845).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HARS2 | NM_012208.4 | c.100C>A | p.Gln34Lys | missense_variant | 1/13 | ENST00000230771.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HARS2 | ENST00000230771.9 | c.100C>A | p.Gln34Lys | missense_variant | 1/13 | 1 | NM_012208.4 | A1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1396660Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 689262
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
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0
AN:
1396660
Hom.:
Cov.:
30
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AC XY:
0
AN XY:
689262
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 05, 2023 | The c.100C>A (p.Q34K) alteration is located in exon 1 (coding exon 1) of the HARS2 gene. This alteration results from a C to A substitution at nucleotide position 100, causing the glutamine (Q) at amino acid position 34 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;.;.;T;.;T;T;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;.;.;.;.;N;N;N;.
MutationTaster
Benign
D;N;N;N;N;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;.;.;N;.;.;.;N;N
REVEL
Benign
Sift
Benign
T;.;.;T;.;.;.;T;T
Sift4G
Benign
T;.;.;T;.;.;.;T;T
Polyphen
B;.;.;.;.;B;B;.;B
Vest4
MutPred
Gain of ubiquitination at Q34 (P = 0.0114);Gain of ubiquitination at Q34 (P = 0.0114);Gain of ubiquitination at Q34 (P = 0.0114);Gain of ubiquitination at Q34 (P = 0.0114);Gain of ubiquitination at Q34 (P = 0.0114);Gain of ubiquitination at Q34 (P = 0.0114);Gain of ubiquitination at Q34 (P = 0.0114);Gain of ubiquitination at Q34 (P = 0.0114);Gain of ubiquitination at Q34 (P = 0.0114);
MVP
MPC
ClinPred
T
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
Publications
No publications associated with this variant yet.