5-140693331-CAAAAAAA-CAAAAAAAAA

Variant names:

• chr5-140693331-C-CAA
• rs397884519
• NM_012208.4:c.109-244_109-243dupAA

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BS1

The NM_012208.4(HARS2):​c.109-244_109-243dupAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00062 in 568,018 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 21)
  • Exomes 𝑓: 0.00041 (0 hom.)
• Consequence: HARS2 NM_012208.4 intron
• Clinical Significance: Not reported in ClinVar
• 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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00153 (165/108050) while in subpopulation AFR AF= 0.00539 (160/29670). AF 95% confidence interval is 0.00471. There are 0 homozygotes in gnomad4. There are 73 alleles in male gnomad4 subpopulation. Median coverage is 21. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HARS2	NM_012208.4	c.109-244_109-243dupAA		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_109-259insAA		intron_variant	Intron 1 of 12	1	NM_012208.4	ENSP00000230771.3

Frequencies

GnomAD3 genomes AF: 0.00153 AC: 165 AN: 108030 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00540

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000198

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000156

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000399

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000407 AC: 187 AN: 459968 Hom.: 0 AF XY: 0.000409 AC XY: 99 AN XY: 241802

Gnomad4 AFR exome AF: 0.00329

Gnomad4 AMR exome AF: 0.0000541

Gnomad4 ASJ exome AF: 0.000446

Gnomad4 EAS exome AF: 0.000164

Gnomad4 SAS exome AF: 0.000372

Gnomad4 FIN exome AF: 0.000283

Gnomad4 NFE exome AF: 0.000332

Gnomad4 OTH exome AF: 0.000575

GnomAD4 genome AF: 0.00153 AC: 165 AN: 108050 Hom.: 0 Cov.: 21 AF XY: 0.00141 AC XY: 73 AN XY: 51830

Gnomad4 AFR AF: 0.00539

Gnomad4 AMR AF: 0.000198

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000156

Gnomad4 NFE AF: 0.0000399

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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;