5-140693331-CA-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_012208.4(HARS2):c.109-243del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.378 in 530,902 control chromosomes in the GnomAD database, including 3,128 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.29 (3022 hom., cov: 21)
  • Exomes 𝑓: 0.40 (106 hom.)
• Consequence: HARS2 NM_012208.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.135

Genes affected

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 5-140693331-CA-C is Benign according to our data. Variant chr5-140693331-CA-C is described in ClinVar as [Benign]. Clinvar id is 1221130.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.313 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HARS2	NM_012208.4	c.109-243del		intron_variant		ENST00000230771.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HARS2	ENST00000230771.9	c.109-243del		intron_variant		1	NM_012208.4	A1

Frequencies

GnomAD3 genomes AF: 0.287 AC: 30960 AN: 107818 Hom.: 3023 Cov.: 21

Gnomad AFR AF: 0.319

Gnomad AMI AF: 0.223

Gnomad AMR AF: 0.273

Gnomad ASJ AF: 0.291

Gnomad EAS AF: 0.202

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.355

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.265

GnomAD4 exome AF: 0.402 AC: 169919 AN: 423060 Hom.: 106 AF XY: 0.400 AC XY: 88974 AN XY: 222396

Gnomad4 AFR exome AF: 0.400

Gnomad4 AMR exome AF: 0.405

Gnomad4 ASJ exome AF: 0.402

Gnomad4 EAS exome AF: 0.405

Gnomad4 SAS exome AF: 0.393

Gnomad4 FIN exome AF: 0.414

Gnomad4 NFE exome AF: 0.401

Gnomad4 OTH exome AF: 0.406

GnomAD4 genome AF: 0.287 AC: 30962 AN: 107842 Hom.: 3022 Cov.: 21 AF XY: 0.293 AC XY: 15133 AN XY: 51728

Gnomad4 AFR AF: 0.319

Gnomad4 AMR AF: 0.272

Gnomad4 ASJ AF: 0.291

Gnomad4 EAS AF: 0.202

Gnomad4 SAS AF: 0.244

Gnomad4 FIN AF: 0.355

Gnomad4 NFE AF: 0.273

Gnomad4 OTH AF: 0.265

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 06, 2019

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs397884519; hg19: chr5-140072916;