rs140540222

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_012208.4(HARS2):​c.448C>A​(p.Arg150Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R150C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

HARS2
NM_012208.4 missense

Scores

12
6
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.79
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr5-140695556-C-T is described in Lovd as [Likely_pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.889

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HARS2NM_012208.4 linkc.448C>A p.Arg150Ser missense_variant Exon 5 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.448C>A p.Arg150Ser missense_variant Exon 5 of 13 1 NM_012208.4 ENSP00000230771.3 P49590-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000410
AC:
6
AN:
1461860
Hom.:
0
Cov.:
33
AF XY:
0.00000413
AC XY:
3
AN XY:
727230
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.87
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.27
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.70
D;.;D;.;.;.;.;D;D;.
Eigen
Pathogenic
0.78
Eigen_PC
Pathogenic
0.72
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.94
.;.;D;.;D;D;D;.;D;D
M_CAP
Uncertain
0.15
D
MetaRNN
Pathogenic
0.89
D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.29
D
MutationAssessor
Pathogenic
3.3
M;.;.;.;.;.;.;M;M;.
PrimateAI
Uncertain
0.58
T
PROVEAN
Pathogenic
-5.7
D;.;D;.;.;.;.;.;.;D
REVEL
Pathogenic
0.66
Sift
Pathogenic
0.0
D;.;D;.;.;.;.;.;.;D
Sift4G
Pathogenic
0.0010
D;.;.;.;.;.;.;.;.;D
Polyphen
1.0
D;.;.;.;.;.;.;D;D;.
Vest4
0.90
MutPred
0.76
Loss of methylation at R150 (P = 0.0385);.;.;.;Loss of methylation at R150 (P = 0.0385);.;.;Loss of methylation at R150 (P = 0.0385);Loss of methylation at R150 (P = 0.0385);.;
MVP
0.90
MPC
0.69
ClinPred
1.0
D
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-140075141; API