rs752472621

Positions:

chr5-140697588-G-A

Variant summary

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

The NM_012208.4(HARS2):c.1217G>A(p.Arg406Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,300 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: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

HARS2
NM_012208.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 8.03

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]

HARS2 links:

Genome browser will be placed here

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=0.33559543).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HARS2	NM_012208.4 linkuse as main transcript	c.1217G>A	p.Arg406Gln	missense_variant	11/13	ENST00000230771.9	NP_036340.1	P49590-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HARS2	ENST00000230771.9 linkuse as main transcript	c.1217G>A	p.Arg406Gln	missense_variant	11/13	1	NM_012208.4	ENSP00000230771.3		P49590-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000477

AC:

AN:

251468

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000615

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461204

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726974

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 13, 2017

Variant classified as Uncertain Significance - Favor Benign. The p.Arg406Gln var iant in HARS2 has not been previously reported in individuals with Perrault synd rome, but has been identified in 0.1% (4/30782) of South Asian and 0.1% (6/11168 0) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gn omad.broadinstitute.org; dbSNP rs752472621). Although this variant has been see n in the general population, its frequency is not high enough to rule out a path ogenic role. Computational prediction tools and conservation analyses suggest th at this variant may not impact the protein, though this information is not predi ctive enough to rule out pathogenicity. In summary, while the clinical significa nce of the p.Arg406Gln variant is uncertain, these data suggest that it is more likely to be benign. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 24, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.42

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;.;.;.;.;.;.;T;T;.;T

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

.;.;.;D;D;D;D;.;D;D;D

M_CAP

Benign

0.027

MetaRNN

Benign

0.34

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Uncertain

2.5

M;.;.;.;.;.;.;M;M;.;.

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-3.6

D;.;.;.;.;.;.;.;.;D;D

REVEL

Benign

0.25

Sift

Benign

0.034

D;.;.;.;.;.;.;.;.;D;D

Sift4G

Uncertain

0.031

D;.;.;.;.;.;.;.;.;D;D

Polyphen

0.82

P;.;.;.;.;.;.;P;P;.;P

Vest4

0.20

MVP

0.62

MPC

0.21

ClinPred

0.55

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.37

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over