rs34790864

chr5-140675067-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002109.6(HARS1):c.1261C>G(p.Leu421Val) variant causes a missense change. The variant allele was found at a frequency of 0.000617 in 1,613,472 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (2 hom.)
• Consequence: HARS1 NM_002109.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.67

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0090326965).
• BP6: Variant 5-140675067-G-C is Benign according to our data. Variant chr5-140675067-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 540208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-140675067-G-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00352 (536/152236) while in subpopulation AFR AF= 0.0124 (514/41536). AF 95% confidence interval is 0.0115. There are 3 homozygotes in gnomad4. There are 245 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HARS1	NM_002109.6	c.1261C>G	p.Leu421Val	missense_variant	11/13	ENST00000504156.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HARS1	ENST00000504156.7	c.1261C>G	p.Leu421Val	missense_variant	11/13	1	NM_002109.6	P3

Frequencies

GnomAD3 genomes AF: 0.00344 AC: 524 AN: 152118 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000983

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: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000851 AC: 214 AN: 251376 Hom.: 2 AF XY: 0.000596 AC XY: 81 AN XY: 135856

Gnomad AFR exome AF: 0.0124

Gnomad AMR exome AF: 0.000318

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: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000315 AC: 460 AN: 1461236 Hom.: 2 Cov.: 30 AF XY: 0.000264 AC XY: 192 AN XY: 726940

Gnomad4 AFR exome AF: 0.0117

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.000613

GnomAD4 genome AF: 0.00352 AC: 536 AN: 152236 Hom.: 3 Cov.: 32 AF XY: 0.00329 AC XY: 245 AN XY: 74420

Gnomad4 AFR AF: 0.0124

Gnomad4 AMR AF: 0.000982

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000895 Hom.: 0

Bravo AF: 0.00417

ESP6500AA AF: 0.0145 AC: 64

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00112 AC: 136

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	HARS1: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 03, 2019

The p.Leu421Val variant in HARS is classified as benign because it has been iden tified in 1.2% (307/24962) of African chromosomes by gnomAD (http://gnomad.broad institute.org). ACMG/AMP criteria applied: BA1. -

Usher syndrome type 3B Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.15
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;D;.;D;D;D;D;D
MetaRNN	Benign	0.0090	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.055	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.5	N;N;.;N;N;N;N;N
REVEL	Uncertain	0.44
Sift	Benign	0.12	T;T;.;T;T;T;T;T
Sift4G	Benign	0.14	T;T;.;T;T;T;T;T
Polyphen		0.11, 0.96, 0.20	.;B;D;D;.;.;.;B
Vest4		0.69
MVP		0.85
MPC		0.46
ClinPred		0.029	T
GERP RS		4.3
Varity_R		0.48
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs34790864; hg19: chr5-140054652;