dbSNP rs397884519: HARS2:c.109-249_109-243delAAAAAAA (chr5-140693331-CAAAAAAA-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_012208.4(HARS2):c.109-249_109-243delAAAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 21)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HARS2
NM_012208.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.11

Publications

0 publications found

Variant links:

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

HARS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HARS2	NM_012208.4	MANE Select	c.109-249_109-243delAAAAAAA	intron	N/A	NP_036340.1	P49590-1
HARS2	NM_001363535.2		c.109-149_109-143delAAAAAAA	intron	N/A	NP_001350464.1	A0A2R8Y5P7
HARS2	NM_001278731.2		c.109-593_109-587delAAAAAAA	intron	N/A	NP_001265660.1	P49590-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HARS2	ENST00000230771.9	TSL:1 MANE Select	c.109-259_109-253delAAAAAAA	intron	N/A	ENSP00000230771.3	P49590-1
HARS2	ENST00000510104.5	TSL:1	n.109-159_109-153delAAAAAAA	intron	N/A	ENSP00000423530.1	D6R9M5
HARS2	ENST00000926034.1		c.109-259_109-253delAAAAAAA	intron	N/A	ENSP00000596093.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000217

AC:

AN:

460536

Hom.:

AF XY:

0.00

AC XY:

AN XY:

242110

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

12530

American (AMR)

AF:

0.00

AC:

AN:

18492

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13468

East Asian (EAS)

AF:

0.00

AC:

AN:

30480

South Asian (SAS)

AF:

0.00

AC:

AN:

43100

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28280

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1964

European-Non Finnish (NFE)

AF:

0.00000350

AC:

AN:

286122

Other (OTH)

AF:

0.00

AC:

AN:

26100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.1

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over