5-140698546-G-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_012208.4(HARS2):c.1515G>T(p.Glu505Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000546 in 1,611,890 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000066 ( 1 hom., cov: 33)

Exomes 𝑓: 0.000053 ( 1 hom. )

Consequence

HARS2
NM_012208.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 0.256

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:

ZMAT2 (HGNC:26433): (zinc finger matrin-type 2) Predicted to enable DNA binding activity and zinc ion binding activity. Involved in mRNA splicing, via spliceosome. Located in nucleus. Part of U2-type precatalytic spliceosome. [provided by Alliance of Genome Resources, Apr 2022]

ZMAT2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02610445).

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000534 (78/1459564) while in subpopulation EAS AF= 0.000605 (24/39686). AF 95% confidence interval is 0.000416. There are 1 homozygotes in gnomad4_exome. There are 42 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HARS2	NM_012208.4 link	c.1515G>T	p.Glu505Asp	missense_variant	Exon 13 of 13	ENST00000230771.9	NP_036340.1	P49590-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HARS2	ENST00000230771.9 link	c.1515G>T	p.Glu505Asp	missense_variant	Exon 13 of 13	1	NM_012208.4	ENSP00000230771.3		P49590-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000835

AC:

AN:

251482

Hom.:

AF XY:

0.0000809

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000534

AC:

AN:

1459564

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

726304

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000605

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.000812

GnomAD4 genome

AF:

0.0000656

AC:

AN:

152326

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000946

Bravo

AF:

0.0000378

ExAC

AF:

0.0000906

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

May 29, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Mar 26, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 505 of the HARS2 protein (p.Glu505Asp). This variant is present in population databases (rs370053420, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with HARS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 517495). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The aspartic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Uncertain:1

Nov 29, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1515G>T (p.E505D) alteration is located in exon 13 (coding exon 13) of the HARS2 gene. This alteration results from a G to T substitution at nucleotide position 1515, causing the glutamic acid (E) at amino acid position 505 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Jul 25, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Glu505Asp in exon 13 of HARS2: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, elephant, shrew, manatee, tenrec and aardvark have an Asp at this position despite high nearby amino acid conservation. In addition, computational predict ion tools do not suggest a high likelihood of impact to the protein. It has been identified in 0.1% (23/18870) of East Asian chromosomes by the Genome Aggregati on Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs370053420). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.57

CADD

Benign

8.6

DANN

Uncertain

0.98

DEOGEN2

Benign

0.076

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

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.57

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.67

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

M_CAP

Benign

0.0092

MetaRNN

Benign

0.026

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

L;.;.;.;.;.;.;L;L;.;.

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.2

N;.;.;.;.;.;.;.;.;N;N

REVEL

Benign

0.020

Sift

Benign

0.14

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

Sift4G

Benign

0.26

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

Polyphen

0.0010

B;.;.;.;.;.;.;B;B;.;B

Vest4

0.079

MutPred

0.29

Gain of MoRF binding (P = 0.1131);.;.;.;.;.;.;Gain of MoRF binding (P = 0.1131);Gain of MoRF binding (P = 0.1131);.;.;

MVP

0.37

MPC

0.14

ClinPred

0.041

GERP RS

-1.4

Varity_R

0.034

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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