5-140691291-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_002109.6(HARS1):c.14C>A(p.Ala5Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00758 in 1,605,400 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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 0.0058 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0078 (50 hom.)
• Consequence: HARS1 NM_002109.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 3.96

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037422776).
• BP6: Variant 5-140691291-G-T is Benign according to our data. Variant chr5-140691291-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 472991.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Uncertain_significance=1, Likely_benign=1}. Variant chr5-140691291-G-T is described in Lovd as [Benign]. Variant chr5-140691291-G-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HARS1	NM_002109.6	c.14C>A	p.Ala5Glu	missense_variant	1/13	ENST00000504156.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HARS1	ENST00000504156.7	c.14C>A	p.Ala5Glu	missense_variant	1/13	1	NM_002109.6	P3

Frequencies

GnomAD3 genomes AF: 0.00581 AC: 883 AN: 151992 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00167

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00911

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00869

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00543 AC: 1321 AN: 243488 Hom.: 4 AF XY: 0.00546 AC XY: 723 AN XY: 132396

Gnomad AFR exome AF: 0.00162

Gnomad AMR exome AF: 0.00614

Gnomad ASJ exome AF: 0.00758

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00129

Gnomad FIN exome AF: 0.00188

Gnomad NFE exome AF: 0.00790

Gnomad OTH exome AF: 0.00937

GnomAD4 exome AF: 0.00776 AC: 11276 AN: 1453290 Hom.: 50 Cov.: 31 AF XY: 0.00766 AC XY: 5538 AN XY: 723214

Gnomad4 AFR exome AF: 0.000778

Gnomad4 AMR exome AF: 0.00695

Gnomad4 ASJ exome AF: 0.00904

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00136

Gnomad4 FIN exome AF: 0.00256

Gnomad4 NFE exome AF: 0.00904

Gnomad4 OTH exome AF: 0.00701

GnomAD4 genome AF: 0.00582 AC: 885 AN: 152110 Hom.: 4 Cov.: 32 AF XY: 0.00561 AC XY: 417 AN XY: 74358

Gnomad4 AFR AF: 0.00166

Gnomad4 AMR AF: 0.00910

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000832

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.00872

Gnomad4 OTH AF: 0.0119

Alfa AF: 0.00774 Hom.: 8

Bravo AF: 0.00635

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.0105 AC: 90

ExAC AF: 0.00563 AC: 684

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00993

EpiControl AF: 0.00748

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 11, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	HARS1: BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2018	This variant is associated with the following publications: (PMID: 22930593) -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 02, 2021	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Usher syndrome type 3B Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jan 15, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	22
Dann	Benign	0.71
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.76	T;T;.;T;T;T;T;T
MetaRNN	Benign	0.0037	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L;.;L;L;L;L;.;.
MutationTaster	Benign	0.50	D;D;D;N;N;N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.45	N;N;.;N;N;N;N;N
REVEL	Benign	0.046
Sift	Benign	0.62	T;T;.;T;T;T;D;D
Sift4G	Benign	0.81	T;T;.;T;T;T;T;.
Polyphen		0.32, 0.37	.;B;B;B;.;.;B;.
Vest4		0.33
MVP		0.53
MPC		0.48
ClinPred		0.0075	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.074
gMVP		0.35

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: rs78741041; hg19: chr5-140070876;