rs147288996

chr5-140677924-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002109.6(HARS1):c.614G>A(p.Gly205Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00223 in 1,607,964 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G205G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0028 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0022 (12 hom.)
• Consequence: HARS1 NM_002109.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 7.57

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010127872).
• BP6: Variant 5-140677924-C-T is Benign according to our data. Variant chr5-140677924-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 226652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-140677924-C-T is described in Lovd as [Benign]. Variant chr5-140677924-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HARS1	NM_002109.6	c.614G>A	p.Gly205Asp	missense_variant	6/13	ENST00000504156.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HARS1	ENST00000504156.7	c.614G>A	p.Gly205Asp	missense_variant	6/13	1	NM_002109.6	P3

Frequencies

GnomAD3 genomes AF: 0.00276 AC: 419 AN: 151792 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.000363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000329

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00313

Gnomad FIN AF: 0.0211

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00222

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00284 AC: 715 AN: 251372 Hom.: 5 AF XY: 0.00283 AC XY: 384 AN XY: 135866

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00127

Gnomad FIN exome AF: 0.0175

Gnomad NFE exome AF: 0.00226

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00218 AC: 3167 AN: 1456054 Hom.: 12 Cov.: 29 AF XY: 0.00216 AC XY: 1566 AN XY: 724832

Gnomad4 AFR exome AF: 0.000360

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00137

Gnomad4 FIN exome AF: 0.0138

Gnomad4 NFE exome AF: 0.00189

Gnomad4 OTH exome AF: 0.00201

GnomAD4 genome AF: 0.00276 AC: 419 AN: 151910 Hom.: 3 Cov.: 31 AF XY: 0.00398 AC XY: 295 AN XY: 74206

Gnomad4 AFR AF: 0.000362

Gnomad4 AMR AF: 0.000328

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00313

Gnomad4 FIN AF: 0.0211

Gnomad4 NFE AF: 0.00222

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00200 Hom.: 1

Bravo AF: 0.00126

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00257 AC: 312

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00316

EpiControl AF: 0.00255

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2018	This variant is associated with the following publications: (PMID: 22930593, 26264438) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	HARS1: BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 17, 2016

p.Gly205Asp in exon 6 of HARS: This variant is not expected to have clinical sig nificance because it has been identified in 1.7% (115/6610) of Finnish chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs147288996). -

Usher syndrome type 3B Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.020
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D;.;D;D;D;D;D
MetaRNN	Benign	0.010	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.29	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.7	D;D;.;D;D;D;D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.027	D;D;.;D;D;D;D;D
Sift4G	Uncertain	0.018	D;D;.;D;D;D;D;D
Polyphen		0.73, 1.0, 0.73	.;P;D;D;.;.;.;P
Vest4		0.71
MVP		0.89
MPC		1.2
ClinPred		0.054	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs147288996; hg19: chr5-140057509;