5-140691291-G-T

Variant names:

• chr5-140691291-G-T
• rs78741041
• NM_002109.6:c.14C>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 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. 13/21 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
• Publications: 7 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]

HARS2 (HGNC:4817): (histidyl-tRNA synthetase 2, mitochondrial) Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. The protein encoded by this gene is an enzyme belonging to the class II family of aminoacyl-tRNA synthetases. Functioning in the synthesis of histidyl-transfer RNA, the enzyme plays an accessory role in the regulation of protein biosynthesis. The gene is located in a head-to-head orientation with HARS on chromosome five, where the homologous genes likely share a bidirectional promoter. Mutations in this gene are associated with the pathogenesis of Perrault syndrome, which involves ovarian dysgenesis and sensorineural hearing loss. Alternative splicing results in multiple transcript variants of this gene. [provided by RefSeq, Jul 2013]

HARS2 Gene-Disease associations (from GenCC):

• Perrault syndrome 2

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• Perrault syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 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 VariationId is 472991.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00582 (885/152110) while in subpopulation AMR AF = 0.0091 (139/15274). AF 95% confidence interval is 0.00814. There are 4 homozygotes in GnomAd4. There are 417 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002109.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HARS1	NM_002109.6	MANE Select	c.14C>A	p.Ala5Glu	missense	Exon 1 of 13	NP_002100.2
	HARS1	NM_001258041.3		c.14C>A	p.Ala5Glu	missense	Exon 1 of 13	NP_001244970.1	P12081-4
	HARS1	NM_001258040.3		c.14C>A	p.Ala5Glu	missense	Exon 1 of 12	NP_001244969.1	P12081-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HARS1	ENST00000504156.7	TSL:1 MANE Select	c.14C>A	p.Ala5Glu	missense	Exon 1 of 13	ENSP00000425634.1	P12081-1
	HARS1	ENST00000457527.6	TSL:1	c.14C>A	p.Ala5Glu	missense	Exon 1 of 13	ENSP00000387893.2	P12081-4
	HARS1	ENST00000942727.1		c.14C>A	p.Ala5Glu	missense	Exon 1 of 14	ENSP00000612786.1

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

GnomAD2 exomes AF: 0.00543 AC: 1321 AN: 243488 AF XY: 0.00546

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 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

African (AFR) AF: 0.000778 AC: 26 AN: 33430

American (AMR) AF: 0.00695 AC: 309 AN: 44462

Ashkenazi Jewish (ASJ) AF: 0.00904 AC: 235 AN: 26000

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00136 AC: 117 AN: 86022

European-Finnish (FIN) AF: 0.00256 AC: 121 AN: 47290

Middle Eastern (MID) AF: 0.000870 AC: 5 AN: 5746

European-Non Finnish (NFE) AF: 0.00904 AC: 10041 AN: 1110450

Other (OTH) AF: 0.00701 AC: 422 AN: 60242

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

African (AFR) AF: 0.00166 AC: 69 AN: 41508

American (AMR) AF: 0.00910 AC: 139 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000832 AC: 4 AN: 4810

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00872 AC: 593 AN: 67984

Other (OTH) AF: 0.0119 AC: 25 AN: 2106

Alfa AF: 0.00749 Hom.: 13

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	2	not specified (2)
-	-	2	Usher syndrome type 3B (2)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PhyloP100		4.0
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.046
Sift	Benign	0.62	T
Sift4G	Benign	0.81	T
Polyphen		0.32	B
Vest4		0.33
MVP		0.53
MPC		0.48
ClinPred		0.0075	T
GERP RS		3.8
PromoterAI		0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.074
gMVP		0.35
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs78741041; hg19: chr5-140070876;