5-140697311-G-T

Position:

chr5-140697311-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_012208.4(HARS2):c.1102G>T(p.Val368Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

HARS2
NM_012208.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic no assertion criteria provided P:2O:1

Conservation

PhyloP100: 9.65

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.825

PP5

Variant 5-140697311-G-T is Pathogenic according to our data. Variant chr5-140697311-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208286.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-140697311-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HARS2	NM_012208.4 linkuse as main transcript	c.1102G>T	p.Val368Leu	missense_variant	10/13	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.1102G>T	p.Val368Leu	missense_variant	10/13	1	NM_012208.4	ENSP00000230771.3		P49590-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251462

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727240

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

AF:

0.00000657

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Perrault syndrome 2

Pathogenic:2

Likely pathogenic, no assertion criteria provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	Jun 27, 2013	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 19, 2011	- -

Perrault syndrome

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

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

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

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

M_CAP

Benign

0.075

MetaRNN

Pathogenic

0.83

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.0092

MutationAssessor

Uncertain

2.6

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

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-2.8

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

REVEL

Uncertain

0.56

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0020

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

Polyphen

1.0

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

Vest4

0.86

MutPred

0.67

Gain of helix (P = 0.062);.;.;.;.;.;.;Gain of helix (P = 0.062);Gain of helix (P = 0.062);.;.;

MVP

0.93

MPC

0.44

ClinPred

0.93

GERP RS

5.7

Varity_R

0.82

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