NM_020320.5:c.703G>A

Variant names:

• chr6-87530852-C-T
• rs35862137
• NM_020320.5:c.703G>A

Variant summary

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

The NM_020320.5(RARS2):​c.703G>A​(p.Val235Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0419 in 1,614,188 control chromosomes in the GnomAD database, including 1,695 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V235V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.030 (104 hom., cov: 33)
  • Exomes 𝑓: 0.043 (1591 hom.)
• Consequence: RARS2 NM_020320.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.810
• Publications: 19 publications found

Genes affected

RARS2 (HGNC:21406): (arginyl-tRNA synthetase 2, mitochondrial) This nuclear gene encodes a protein that localizes to the mitochondria, where it catalyzes the transfer of L-arginine to its cognate tRNA, an important step in translation of mitochondrially-encoded proteins. Defects in this gene are a cause of pontocerebellar hypoplasia type 6 (PCH6). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

RARS2 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• pontocerebellar hypoplasia type 6

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Laboratory for Molecular Medicine, Ambry Genetics
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029790401).
• BP6: Variant 6-87530852-C-T is Benign according to our data. Variant chr6-87530852-C-T is described in ClinVar as Benign. ClinVar VariationId is 130098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0301 (4586/152326) while in subpopulation NFE AF = 0.0446 (3034/68030). AF 95% confidence interval is 0.0433. There are 104 homozygotes in GnomAd4. There are 2250 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 104 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020320.5. 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
	RARS2	NM_020320.5	MANE Select	c.703G>A	p.Val235Met	missense	Exon 9 of 20	NP_064716.2	Q5T160
	RARS2	NM_001350505.2		c.703G>A	p.Val235Met	missense	Exon 9 of 21	NP_001337434.1	A0A8I5KWC6
	RARS2	NM_001350506.2		c.178G>A	p.Val60Met	missense	Exon 9 of 21	NP_001337435.1	A0A8I5KPZ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARS2	ENST00000369536.10	TSL:1 MANE Select	c.703G>A	p.Val235Met	missense	Exon 9 of 20	ENSP00000358549.5	Q5T160
	RARS2	ENST00000686154.1		c.-538G>A		5_prime_UTR_premature_start_codon_gain	Exon 6 of 19	ENSP00000508436.1	A0A8I5KXM9
	RARS2	ENST00000689206.1		c.-237G>A		5_prime_UTR_premature_start_codon_gain	Exon 9 of 21	ENSP00000510495.1	A0A8I5KXM9

Frequencies

GnomAD3 genomes AF: 0.0302 AC: 4590 AN: 152208 Hom.: 104 Cov.: 33

Gnomad AFR AF: 0.00815

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0264

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0391

Gnomad FIN AF: 0.0480

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0446

Gnomad OTH AF: 0.0287

GnomAD2 exomes AF: 0.0323 AC: 8110 AN: 251472 AF XY: 0.0342

Gnomad AFR exome AF: 0.00837

Gnomad AMR exome AF: 0.0170

Gnomad ASJ exome AF: 0.0122

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.0494

Gnomad NFE exome AF: 0.0413

Gnomad OTH exome AF: 0.0319

GnomAD4 exome AF: 0.0432 AC: 63117 AN: 1461862 Hom.: 1591 Cov.: 32 AF XY: 0.0431 AC XY: 31367 AN XY: 727240

African (AFR) AF: 0.00654 AC: 219 AN: 33480

American (AMR) AF: 0.0166 AC: 742 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0122 AC: 318 AN: 26134

East Asian (EAS) AF: 0.000605 AC: 24 AN: 39694

South Asian (SAS) AF: 0.0419 AC: 3613 AN: 86258

European-Finnish (FIN) AF: 0.0503 AC: 2687 AN: 53420

Middle Eastern (MID) AF: 0.0163 AC: 94 AN: 5768

European-Non Finnish (NFE) AF: 0.0478 AC: 53185 AN: 1111990

Other (OTH) AF: 0.0370 AC: 2235 AN: 60394

GnomAD4 genome AF: 0.0301 AC: 4586 AN: 152326 Hom.: 104 Cov.: 33 AF XY: 0.0302 AC XY: 2250 AN XY: 74492

African (AFR) AF: 0.00813 AC: 338 AN: 41570

American (AMR) AF: 0.0263 AC: 403 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.0391 AC: 189 AN: 4828

European-Finnish (FIN) AF: 0.0480 AC: 509 AN: 10608

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0446 AC: 3034 AN: 68030

Other (OTH) AF: 0.0284 AC: 60 AN: 2114

Alfa AF: 0.0376 Hom.: 453

Bravo AF: 0.0262

TwinsUK AF: 0.0499 AC: 185

ALSPAC AF: 0.0527 AC: 203

ESP6500AA AF: 0.0111 AC: 49

ESP6500EA AF: 0.0435 AC: 374

ExAC AF: 0.0321 AC: 3894

Asia WGS AF: 0.0150 AC: 52 AN: 3478

EpiCase AF: 0.0385

EpiControl AF: 0.0364

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Pontocerebellar hypoplasia type 6 (4)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	RARS2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.088
DANN	Benign	0.92
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.81
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.17	N
REVEL	Benign	0.068
Sift	Benign	0.088	T
Sift4G	Benign	0.083	T
Polyphen		0.0	B
Vest4		0.21
MPC		0.11
ClinPred		0.0012	T
GERP RS		-5.6
Varity_R		0.033
gMVP		0.13
Mutation Taster		=98/2	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: rs35862137; hg19: chr6-88240570; COSMIC: COSV65762051;