rs148516171

Variant names:

• chr5-140691233-C-T
• rs148516171
• NM_002109.6:c.72G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-140691233-C-T
• chr5-140691233-C-G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS1

The NM_002109.6(HARS1):​c.72G>A​(p.Gln24Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000613 in 1,606,750 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00052 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (0 hom.)
• Consequence: HARS1 NM_002109.6 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.67
• Publications: 0 publications found

Genes affected

HARS1 (HGNC:4816): (histidyl-tRNA synthetase 1) Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. The protein encoded by this gene is a cytoplasmic enzyme which belongs to the class II family of aminoacyl-tRNA synthetases. The enzyme is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. The gene is located in a head-to-head orientation with HARSL on chromosome five, where the homologous genes share a bidirectional promoter. The gene product is a frequent target of autoantibodies in the human autoimmune disease polymyositis/dermatomyositis. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

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: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP6: Variant 5-140691233-C-T is Benign according to our data. Variant chr5-140691233-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 540209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.67 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00052 (79/152040) while in subpopulation AMR AF = 0.00184 (28/15242). AF 95% confidence interval is 0.00131. There are 1 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002109.6. 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
	HARS1	NM_002109.6	MANE Select	c.72G>A	p.Gln24Gln	synonymous	Exon 1 of 13	NP_002100.2
	HARS1	NM_001258041.3		c.72G>A	p.Gln24Gln	synonymous	Exon 1 of 13	NP_001244970.1	P12081-4
	HARS1	NM_001258040.3		c.72G>A	p.Gln24Gln	synonymous	Exon 1 of 12	NP_001244969.1	P12081-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HARS1	ENST00000504156.7	TSL:1 MANE Select	c.72G>A	p.Gln24Gln	synonymous	Exon 1 of 13	ENSP00000425634.1	P12081-1
	HARS1	ENST00000457527.6	TSL:1	c.72G>A	p.Gln24Gln	synonymous	Exon 1 of 13	ENSP00000387893.2	P12081-4
	HARS1	ENST00000942727.1		c.72G>A	p.Gln24Gln	synonymous	Exon 1 of 14	ENSP00000612786.1

Frequencies

GnomAD3 genomes AF: 0.000520 AC: 79 AN: 152040 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

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: 0.000676

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000329 AC: 81 AN: 245972 AF XY: 0.000352

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000320

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000587

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000623 AC: 906 AN: 1454710 Hom.: 0 Cov.: 30 AF XY: 0.000651 AC XY: 471 AN XY: 723876

African (AFR) AF: 0.0000598 AC: 2 AN: 33434

American (AMR) AF: 0.000382 AC: 17 AN: 44534

Ashkenazi Jewish (ASJ) AF: 0.000192 AC: 5 AN: 26036

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86068

European-Finnish (FIN) AF: 0.0000207 AC: 1 AN: 48364

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5756

European-Non Finnish (NFE) AF: 0.000755 AC: 839 AN: 1110592

Other (OTH) AF: 0.000681 AC: 41 AN: 60240

GnomAD4 genome AF: 0.000520 AC: 79 AN: 152040 Hom.: 1 Cov.: 32 AF XY: 0.000539 AC XY: 40 AN XY: 74258

African (AFR) AF: 0.000121 AC: 5 AN: 41398

American (AMR) AF: 0.00184 AC: 28 AN: 15242

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000676 AC: 46 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000279 Hom.: 0

Bravo AF: 0.000442

EpiCase AF: 0.000654

EpiControl AF: 0.000950

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	HARS1-related disorder (1)
-	-	1	not specified (1)
-	-	1	Usher syndrome type 3B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	14
DANN	Benign	0.91
PhyloP100		1.7
PromoterAI		0.018	Neutral
Mutation Taster		=99/1	polymorphism

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: rs148516171; hg19: chr5-140070818; COSMIC: COSV100047694; COSMIC: COSV100047694;