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. The variant received -4 ACMG points: 0P and 4B. 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
• Publications: 0 publications found

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]

HARS2 Gene-Disease associations (from GenCC):

• Perrault syndrome 2

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• 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 the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012208.4. 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
	HARS2	NM_012208.4	MANE Select	c.109-244_109-243dupAA		intron	N/A	NP_036340.1	P49590-1
	HARS2	NM_001363535.2		c.109-144_109-143dupAA		intron	N/A	NP_001350464.1	A0A2R8Y5P7
	HARS2	NM_001278731.2		c.109-588_109-587dupAA		intron	N/A	NP_001265660.1	P49590-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HARS2	ENST00000230771.9	TSL:1 MANE Select	c.109-260_109-259insAA		intron	N/A	ENSP00000230771.3	P49590-1
	HARS2	ENST00000510104.5	TSL:1	n.109-160_109-159insAA		intron	N/A	ENSP00000423530.1	D6R9M5
	HARS2	ENST00000926034.1		c.109-260_109-259insAA		intron	N/A	ENSP00000596093.1

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00329 AC: 41 AN: 12480

American (AMR) AF: 0.0000541 AC: 1 AN: 18478

Ashkenazi Jewish (ASJ) AF: 0.000446 AC: 6 AN: 13456

East Asian (EAS) AF: 0.000164 AC: 5 AN: 30456

South Asian (SAS) AF: 0.000372 AC: 16 AN: 43050

European-Finnish (FIN) AF: 0.000283 AC: 8 AN: 28260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1964

European-Non Finnish (NFE) AF: 0.000332 AC: 95 AN: 285754

Other (OTH) AF: 0.000575 AC: 15 AN: 26070

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.00539 AC: 160 AN: 29670

American (AMR) AF: 0.000198 AC: 2 AN: 10102

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2734

East Asian (EAS) AF: 0.00 AC: 0 AN: 3532

South Asian (SAS) AF: 0.00 AC: 0 AN: 3220

European-Finnish (FIN) AF: 0.000156 AC: 1 AN: 6430

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 160

European-Non Finnish (NFE) AF: 0.0000399 AC: 2 AN: 50166

Other (OTH) AF: 0.00 AC: 0 AN: 1422

Alfa AF: 0.00 Hom.: 59

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.14

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397884519; hg19: chr5-140072916;