Genetic Variant NM_012208.4:c.109-245_109-243dupAAA (chr5-140693331-C-CAAA) – 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.109-245_109-243dupAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 460,502 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 0.0 ( 0 hom., cov: 21)

Exomes 𝑓: 0.000017 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HARS2
NM_012208.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.135

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: 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.109-245_109-243dupAAA	intron	N/A	NP_036340.1	P49590-1
HARS2	NM_001363535.2		c.109-145_109-143dupAAA	intron	N/A	NP_001350464.1	A0A2R8Y5P7
HARS2	NM_001278731.2		c.109-589_109-587dupAAA	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.109-260_109-259insAAA	intron	N/A	ENSP00000230771.3	P49590-1
HARS2	ENST00000510104.5	TSL:1	n.109-160_109-159insAAA	intron	N/A	ENSP00000423530.1	D6R9M5
HARS2	ENST00000926034.1		c.109-260_109-259insAAA	intron	N/A	ENSP00000596093.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

108054

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000174

AC:

AN:

460502

Hom.:

AF XY:

0.00000413

AC XY:

AN XY:

242084

show subpopulations

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

African (AFR)

AF:

0.0000798

AC:

AN:

12528

American (AMR)

AF:

0.00

AC:

AN:

18492

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13466

East Asian (EAS)

AF:

0.0000328

AC:

AN:

30480

South Asian (SAS)

AF:

0.00

AC:

AN:

43096

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28276

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1964

European-Non Finnish (NFE)

AF:

0.0000175

AC:

AN:

286102

Other (OTH)

AF:

0.0000383

AC:

AN:

26098

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.244

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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

108054

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

51786

African (AFR)

AF:

0.00

AC:

AN:

29628

American (AMR)

AF:

0.00

AC:

AN:

10098

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2734

East Asian (EAS)

AF:

0.00

AC:

AN:

3538

South Asian (SAS)

AF:

0.00

AC:

AN:

3228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6438

Middle Eastern (MID)

AF:

0.00

AC:

AN:

180

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

50180

Other (OTH)

AF:

0.00

AC:

AN:

1416

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.14

Mutation Taster

=100/0

polymorphism

(source)

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