5-140697314-G-C

Variant names:

• chr5-140697314-G-C
• rs61736946
• NM_012208.4:c.1105G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_012208.4(HARS2):​c.1105G>C​(p.Gly369Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000514 in 1,614,126 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (5 hom.)
• Consequence: HARS2 NM_012208.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.55
• Publications: 5 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013633937).
• BP6: Variant 5-140697314-G-C is Benign according to our data. Variant chr5-140697314-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 214547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00256 (390/152248) while in subpopulation AFR AF = 0.00891 (370/41534). AF 95% confidence interval is 0.00816. There are 2 homozygotes in GnomAd4. There are 205 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.1105G>C	p.Gly369Arg	missense	Exon 10 of 13	NP_036340.1	P49590-1
	HARS2	NM_001363535.2		c.1123G>C	p.Gly375Arg	missense	Exon 11 of 14	NP_001350464.1	A0A2R8Y5P7
	HARS2	NM_001278731.2		c.1030G>C	p.Gly344Arg	missense	Exon 9 of 12	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.1105G>C	p.Gly369Arg	missense	Exon 10 of 13	ENSP00000230771.3	P49590-1
	HARS2	ENST00000926034.1		c.1135G>C	p.Gly379Arg	missense	Exon 10 of 13	ENSP00000596093.1
	HARS2	ENST00000645065.1		c.1123G>C	p.Gly375Arg	missense	Exon 12 of 15	ENSP00000493571.1	A0A2R8Y5P7

Frequencies

GnomAD3 genomes AF: 0.00256 AC: 389 AN: 152130 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00891

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

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: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000672 AC: 169 AN: 251456 AF XY: 0.000515

Gnomad AFR exome AF: 0.00929

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000301 AC: 440 AN: 1461878 Hom.: 5 Cov.: 34 AF XY: 0.000243 AC XY: 177 AN XY: 727240

African (AFR) AF: 0.0111 AC: 372 AN: 33480

American (AMR) AF: 0.000492 AC: 22 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.000729 AC: 44 AN: 60396

GnomAD4 genome AF: 0.00256 AC: 390 AN: 152248 Hom.: 2 Cov.: 32 AF XY: 0.00275 AC XY: 205 AN XY: 74430

African (AFR) AF: 0.00891 AC: 370 AN: 41534

American (AMR) AF: 0.000916 AC: 14 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000444 Hom.: 1

Bravo AF: 0.00309

ESP6500AA AF: 0.00931 AC: 41

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000832 AC: 101

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	HARS2-related disorder (1)
-	-	1	Perrault syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	0.091	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		5.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.98	D
Vest4		0.64
MVP		0.92
MPC		0.23
ClinPred		0.062	T
GERP RS		5.7
Varity_R		0.83
Mutation Taster		=91/9	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: rs61736946; hg19: chr5-140076899;