rs387906639

Variant names:

• chr5-140674776-T-G
• rs387906639
• NM_002109.6:c.1361A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP5 BP4

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). Synonymous variant affecting the same amino acid position (i.e. Y454Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: HARS1 NM_002109.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3
• Conservation: PhyloP100: 4.89
• Publications: 17 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant Charcot-Marie-Tooth disease type 2W

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• Usher syndrome type 3B

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Usher syndrome type 3

  Inheritance: AR Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• 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 VariationId is 29756.
• 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	c.1361A>C	p.Tyr454Ser	missense_variant	Exon 12 of 13	ENST00000504156.7	NP_002100.2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152214 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251444 AF XY: 0.0000147

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461878 Hom.: 0 Cov.: 34 AF XY: 0.0000165 AC XY: 12 AN XY: 727242

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1112000

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74366

African (AFR) AF: 0.0000241 AC: 1 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000351 Hom.: 0

Bravo AF: 0.0000945

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Usher syndrome type 3B Pathogenic:1 Uncertain:2

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. -

Jan 01, 2012

OMIM

Significance: Pathogenic

Review Status: flagged submission

Collection Method: literature only

- -

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	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	26
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	D
LIST_S2	Uncertain	0.96	D;D;.;D;D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.24	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.47	D
MutationAssessor	Uncertain	2.6	.;.;M;M;.;.;.;.
PhyloP100		4.9
PrimateAI	Uncertain	0.63	T
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	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.81
Mutation Taster		=20/80	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs387906639; hg19: chr5-140054361;