5-140693478-TC-T

Variant names:

• chr5-140693478-TC-T
• rs577099650
• NM_012208.4:c.109-111delC

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS1

The NM_012208.4(HARS2):​c.109-111delC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000366 in 1,592,248 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (0 hom.)
• Consequence: HARS2 NM_012208.4 intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.422
• 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: ClinGen, Labcorp Genetics (formerly Invitae)
• Perrault syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 5-140693478-TC-T is Benign according to our data. Variant chr5-140693478-TC-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3048804.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000381 (548/1439920) while in subpopulation NFE AF = 0.000461 (507/1100576). AF 95% confidence interval is 0.000427. There are 0 homozygotes in GnomAdExome4. There are 266 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. 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.109-111delC		intron	N/A	NP_036340.1	P49590-1
	HARS2	NM_001363535.2		c.109-11delC		intron	N/A	NP_001350464.1	A0A2R8Y5P7
	HARS2	NM_001278731.2		c.109-455delC		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.109-111delC		intron	N/A	ENSP00000230771.3	P49590-1
	HARS2	ENST00000510104.5	TSL:1	n.109-11delC		intron	N/A	ENSP00000423530.1	D6R9M5
	HARS2	ENST00000926034.1		c.109-111delC		intron	N/A	ENSP00000596093.1

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000190 AC: 41 AN: 215752 AF XY: 0.000171

Gnomad AFR exome AF: 0.0000753

Gnomad AMR exome AF: 0.0000324

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000374

Gnomad OTH exome AF: 0.000182

GnomAD4 exome AF: 0.000381 AC: 548 AN: 1439920 Hom.: 0 Cov.: 32 AF XY: 0.000372 AC XY: 266 AN XY: 715156

African (AFR) AF: 0.000185 AC: 6 AN: 32404

American (AMR) AF: 0.0000483 AC: 2 AN: 41412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25794

East Asian (EAS) AF: 0.00 AC: 0 AN: 37812

South Asian (SAS) AF: 0.000107 AC: 9 AN: 84110

European-Finnish (FIN) AF: 0.0000571 AC: 3 AN: 52546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.000461 AC: 507 AN: 1100576

Other (OTH) AF: 0.000353 AC: 21 AN: 59532

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74496

African (AFR) AF: 0.000120 AC: 5 AN: 41576

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000391 Hom.: 0

Bravo AF: 0.000298

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	HARS2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs577099650; hg19: chr5-140073063;