rs387906639

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4

The NM_002109.6(HARS1):c.1361A>C(p.Tyr454Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000223 in 1,614,092 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

HARS1
NM_002109.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3

Conservation

PhyloP100: 4.89

Variant links:

Genes affected

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]

HARS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-140674776-T-G is Pathogenic according to our data. Variant chr5-140674776-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 29756.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Pathogenic=2}. Variant chr5-140674776-T-G is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.24100208). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HARS1	NM_002109.6 link	c.1361A>C	p.Tyr454Ser	missense_variant	Exon 12 of 13	ENST00000504156.7	NP_002100.2	P12081-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HARS1	ENST00000504156.7 link	c.1361A>C	p.Tyr454Ser	missense_variant	Exon 12 of 13	1	NM_002109.6	ENSP00000425634.1		P12081-1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.0110

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:

0.0000199

AC:

AN:

251444

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135896

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:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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

Alfa

AF:

0.000100

Hom.:

Bravo

AF:

0.0000945

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Usher syndrome type 3B

Pathogenic:1Uncertain:2

Jan 01, 2012

OMIM

Significance: Pathogenic

Review Status: flagged submission

Collection Method: literature only

- -

Jun 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 454 of the HARS protein (p.Tyr454Ser). This variant is present in population databases (rs387906639, gnomAD 0.006%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 22279824, 31028937). ClinVar contains an entry for this variant (Variation ID: 29756). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HARS protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on HARS function (PMID: 22279524, 28632987). 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. -

Jun 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.1361A>C (p.Tyr454Ser) variant in HARS1 gene has been previously reported in homozygous state in individual affected with Usher syndrome (Whatley M et al. 2020; Abbott JA et al. 2017). The p.Tyr454Ser variant is present with allele frequency of 0.002% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic / Uncertain Significance. Multiple lines of computational evidence (Polyphen - Possibly damaging, SIFT - Tolerated and MutationTaster - Disease causing) predicts conflicting evidence on protein structure and function for this variant. The reference amino acid at this position on HARS1 gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Tyr at position 454 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on HARS function (Abbott JA et al. 2017). Hence for these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). -

Inborn genetic diseases

Pathogenic:1

Oct 16, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1

Oct 16, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Tyr454Ser variant in HARS has been reported in the homozygous state in 3 Amish individual s with childhood-onset progressive profound hearing loss and retinal abnormaliti es consistent with features of Usher syndrome type III (USH3), but they also pre sented with additional clinical manifestations not usually reported in USH3 pati ents including delayed gross motor development, hyperactive patellar tendon refl exes, mild truncal ataxia, and wide-based gait (Puffenberger 2012). The variant was also detected in 1.7% (7/406) of Amish control chromosomes (Puffenberger 201 2), and in 2/30782 South Asian chromosomes by the Genome Aggregation Database (g nomAD, http://gnomad.broadinstitute.org; dbSNP rs387906639). In vitro functional studies provide some evidence that the p.Tyr454Ser variant may impact protein f unction (Puffenberger 2012, Abbott 2017); however, these types of assays may not accurately represent biological function. Computational prediction tools and co nservation analysis do not provide strong support for or against an impact to th e protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Tyr454Ser variant is uncertain. ACMG/AMP Criteria applied: PS3_Supporting, PM3_Supporting, PS3_Supporting (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Uncertain

0.082

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Benign

0.13

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

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

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

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.24

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

MetaSVM

Uncertain

0.47

MutationAssessor

Uncertain

2.6

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

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-7.1

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

REVEL

Pathogenic

0.70

Sift

Benign

0.21

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

Sift4G

Benign

0.22

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

Polyphen

0.65, 0.99, 0.42

.;P;D;D;.;.;.;B

Vest4

0.71

MutPred

0.58

.;.;Gain of disorder (P = 0.0573);Gain of disorder (P = 0.0573);.;.;.;.;

MVP

0.92

MPC

1.4

ClinPred

0.69

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.81

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