chr5-140693331-CA-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_012208.4(HARS2):​c.109-243delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.378 in 530,902 control chromosomes in the GnomAD database, including 3,128 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.29 (3022 hom., cov: 21)
  • Exomes 𝑓: 0.40 (106 hom.)
• Consequence: HARS2 NM_012208.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 5-140693331-CA-C is Benign according to our data. Variant chr5-140693331-CA-C is described in ClinVar as Benign. ClinVar VariationId is 1221130.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.313 is higher than 0.05.

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.109-243delA		intron	N/A	NP_036340.1	P49590-1
	HARS2	NM_001363535.2		c.109-143delA		intron	N/A	NP_001350464.1	A0A2R8Y5P7
	HARS2	NM_001278731.2		c.109-587delA		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.109-259delA		intron	N/A	ENSP00000230771.3	P49590-1
	HARS2	ENST00000510104.5	TSL:1	n.109-159delA		intron	N/A	ENSP00000423530.1	D6R9M5
	HARS2	ENST00000926034.1		c.109-259delA		intron	N/A	ENSP00000596093.1

Frequencies

GnomAD3 genomes AF: 0.287 AC: 30960 AN: 107818 Hom.: 3023 Cov.: 21

Gnomad AFR AF: 0.319

Gnomad AMI AF: 0.223

Gnomad AMR AF: 0.273

Gnomad ASJ AF: 0.291

Gnomad EAS AF: 0.202

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.355

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.265

GnomAD4 exome AF: 0.402 AC: 169919 AN: 423060 Hom.: 106 AF XY: 0.400 AC XY: 88974 AN XY: 222396

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

African (AFR) AF: 0.400 AC: 4608 AN: 11534

American (AMR) AF: 0.405 AC: 6816 AN: 16828

Ashkenazi Jewish (ASJ) AF: 0.402 AC: 5007 AN: 12440

East Asian (EAS) AF: 0.405 AC: 10991 AN: 27160

South Asian (SAS) AF: 0.393 AC: 15590 AN: 39658

European-Finnish (FIN) AF: 0.414 AC: 10857 AN: 26250

Middle Eastern (MID) AF: 0.391 AC: 698 AN: 1784

European-Non Finnish (NFE) AF: 0.401 AC: 105673 AN: 263556

Other (OTH) AF: 0.406 AC: 9679 AN: 23850

⚠️ 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: 0.287 AC: 30962 AN: 107842 Hom.: 3022 Cov.: 21 AF XY: 0.293 AC XY: 15133 AN XY: 51728

African (AFR) AF: 0.319 AC: 9442 AN: 29640

American (AMR) AF: 0.272 AC: 2739 AN: 10068

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 794 AN: 2730

East Asian (EAS) AF: 0.202 AC: 715 AN: 3532

South Asian (SAS) AF: 0.244 AC: 785 AN: 3214

European-Finnish (FIN) AF: 0.355 AC: 2272 AN: 6392

Middle Eastern (MID) AF: 0.253 AC: 41 AN: 162

European-Non Finnish (NFE) AF: 0.273 AC: 13660 AN: 50070

Other (OTH) AF: 0.265 AC: 377 AN: 1420

Alfa AF: 0.0658 Hom.: 59

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs397884519; hg19: chr5-140072916;