chr5-140691706-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001278732.2(HARS2):​c.-253C>A variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000214 in 1,400,416 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: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

HARS2
NM_001278732.2 5_prime_UTR_premature_start_codon_gain

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.18
Variant links:
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]
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 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.28292197).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HARS2NM_012208.4 linkc.58C>A p.Leu20Met missense_variant Exon 1 of 13 ENST00000230771.9 NP_036340.1 P49590-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HARS2ENST00000230771.9 linkc.58C>A p.Leu20Met missense_variant Exon 1 of 13 1 NM_012208.4 ENSP00000230771.3 P49590-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000129
AC:
2
AN:
155386
Hom.:
0
AF XY:
0.0000121
AC XY:
1
AN XY:
82982
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000176
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000214
AC:
3
AN:
1400416
Hom.:
0
Cov.:
31
AF XY:
0.00000145
AC XY:
1
AN XY:
691072
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000836
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Feb 07, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.58C>A (p.L20M) 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 58, causing the leucine (L) at amino acid position 20 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Benign
-0.31
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.11
T;.;.;T;.;T;T;.;T
Eigen
Uncertain
0.23
Eigen_PC
Uncertain
0.25
FATHMM_MKL
Benign
0.74
D
LIST_S2
Benign
0.75
.;.;T;T;T;.;T;T;T
M_CAP
Benign
0.019
T
MetaRNN
Benign
0.28
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.92
T
MutationAssessor
Uncertain
2.4
M;.;.;.;.;M;M;M;.
PrimateAI
Benign
0.42
T
PROVEAN
Benign
-0.11
N;.;.;N;.;.;.;N;N
REVEL
Benign
0.061
Sift
Benign
0.043
D;.;.;D;.;.;.;T;D
Sift4G
Benign
0.16
T;.;.;T;.;.;.;T;D
Polyphen
0.83
P;.;.;.;.;P;P;.;P
Vest4
0.35
MutPred
0.39
Gain of MoRF binding (P = 0.0564);Gain of MoRF binding (P = 0.0564);Gain of MoRF binding (P = 0.0564);Gain of MoRF binding (P = 0.0564);Gain of MoRF binding (P = 0.0564);Gain of MoRF binding (P = 0.0564);Gain of MoRF binding (P = 0.0564);Gain of MoRF binding (P = 0.0564);Gain of MoRF binding (P = 0.0564);
MVP
0.58
MPC
0.39
ClinPred
0.84
D
GERP RS
4.8
Varity_R
0.19

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1410624157; hg19: chr5-140071291; API