5-140693331-CAAAAAAA-CAAAAAAAA

Variant names:

• chr5-140693331-C-CA
• rs397884519
• NM_012208.4:c.109-243dupA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_012208.4(HARS2):​c.109-243dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0284 in 564,180 control chromosomes in the GnomAD database, including 21 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (21 hom., cov: 21)
  • Exomes 𝑓: 0.032 (0 hom.)
• Consequence: HARS2 NM_012208.4 intron
• Clinical Significance: Likely 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-C-CA is Benign according to our data. Variant chr5-140693331-C-CA is described in ClinVar as [Likely_benign]. Clinvar id is 1215658.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0136 (1468/107946) while in subpopulation AFR AF= 0.036 (1068/29654). AF 95% confidence interval is 0.0342. There are 21 homozygotes in gnomad4. There are 730 alleles in male gnomad4 subpopulation. Median coverage is 21. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HARS2	NM_012208.4	c.109-243dupA		intron_variant	Intron 1 of 12	ENST00000230771.9	NP_036340.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HARS2	ENST00000230771.9	c.109-260_109-259insA		intron_variant	Intron 1 of 12	1	NM_012208.4	ENSP00000230771.3

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 1461 AN: 107926 Hom.: 21 Cov.: 21

Gnomad AFR AF: 0.0359

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00942

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.00283

Gnomad SAS AF: 0.00155

Gnomad FIN AF: 0.0150

Gnomad MID AF: 0.0167

Gnomad NFE AF: 0.00271

Gnomad OTH AF: 0.0162

GnomAD4 exome AF: 0.0319 AC: 14544 AN: 456234 Hom.: 0 AF XY: 0.0321 AC XY: 7702 AN XY: 239858

Gnomad4 AFR exome AF: 0.0481

Gnomad4 AMR exome AF: 0.0298

Gnomad4 ASJ exome AF: 0.0394

Gnomad4 EAS exome AF: 0.0336

Gnomad4 SAS exome AF: 0.0271

Gnomad4 FIN exome AF: 0.0332

Gnomad4 NFE exome AF: 0.0312

Gnomad4 OTH exome AF: 0.0332

GnomAD4 genome AF: 0.0136 AC: 1468 AN: 107946 Hom.: 21 Cov.: 21 AF XY: 0.0141 AC XY: 730 AN XY: 51788

Gnomad4 AFR AF: 0.0360

Gnomad4 AMR AF: 0.00941

Gnomad4 ASJ AF: 0.0110

Gnomad4 EAS AF: 0.00283

Gnomad4 SAS AF: 0.00155

Gnomad4 FIN AF: 0.0150

Gnomad4 NFE AF: 0.00271

Gnomad4 OTH AF: 0.0176

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 10, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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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;