rs3757370

Variant names:

• chr6-87521508-T-C
• rs3757370
• NM_020320.5:c.991A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020320.5(RARS2):​c.991A>G​(p.Ile331Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0271 in 1,611,648 control chromosomes in the GnomAD database, including 986 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (115 hom., cov: 32)
  • Exomes 𝑓: 0.027 (871 hom.)
• Consequence: RARS2 NM_020320.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.88
• Publications: 24 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=0.0019848347).
• BP6: Variant 6-87521508-T-C is Benign according to our data. Variant chr6-87521508-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

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.991A>G	p.Ile331Val	missense	Exon 12 of 20	NP_064716.2	Q5T160
	RARS2	NM_001350505.2		c.991A>G	p.Ile331Val	missense	Exon 12 of 21	NP_001337434.1	A0A8I5KWC6
	RARS2	NM_001350506.2		c.466A>G	p.Ile156Val	missense	Exon 12 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.991A>G	p.Ile331Val	missense	Exon 12 of 20	ENSP00000358549.5	Q5T160
	RARS2	ENST00000688532.1		c.-83A>G		5_prime_UTR_premature_start_codon_gain	Exon 9 of 18	ENSP00000510320.1	A0A8I5KVZ5
	RARS2	ENST00000687586.1		c.-87A>G		5_prime_UTR_premature_start_codon_gain	Exon 14 of 22	ENSP00000508441.1	A0A8I5KQK8

Frequencies

GnomAD3 genomes AF: 0.0253 AC: 3844 AN: 152170 Hom.: 115 Cov.: 32

Gnomad AFR AF: 0.00347

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.0476

Gnomad FIN AF: 0.0767

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0260

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.0352 AC: 8831 AN: 250910 AF XY: 0.0365

Gnomad AFR exome AF: 0.00377

Gnomad AMR exome AF: 0.00920

Gnomad ASJ exome AF: 0.0105

Gnomad EAS exome AF: 0.125

Gnomad FIN exome AF: 0.0755

Gnomad NFE exome AF: 0.0245

Gnomad OTH exome AF: 0.0330

GnomAD4 exome AF: 0.0273 AC: 39904 AN: 1459360 Hom.: 871 Cov.: 29 AF XY: 0.0284 AC XY: 20648 AN XY: 726096

African (AFR) AF: 0.00362 AC: 121 AN: 33416

American (AMR) AF: 0.0100 AC: 448 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0114 AC: 297 AN: 26100

East Asian (EAS) AF: 0.117 AC: 4632 AN: 39546

South Asian (SAS) AF: 0.0480 AC: 4139 AN: 86174

European-Finnish (FIN) AF: 0.0737 AC: 3922 AN: 53236

Middle Eastern (MID) AF: 0.0205 AC: 118 AN: 5756

European-Non Finnish (NFE) AF: 0.0222 AC: 24603 AN: 1110140

Other (OTH) AF: 0.0269 AC: 1624 AN: 60282

GnomAD4 genome AF: 0.0252 AC: 3845 AN: 152288 Hom.: 115 Cov.: 32 AF XY: 0.0282 AC XY: 2103 AN XY: 74464

African (AFR) AF: 0.00346 AC: 144 AN: 41564

American (AMR) AF: 0.0140 AC: 215 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3470

East Asian (EAS) AF: 0.116 AC: 601 AN: 5182

South Asian (SAS) AF: 0.0478 AC: 231 AN: 4832

European-Finnish (FIN) AF: 0.0767 AC: 812 AN: 10592

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0260 AC: 1767 AN: 68024

Other (OTH) AF: 0.0161 AC: 34 AN: 2114

Alfa AF: 0.0234 Hom.: 200

Bravo AF: 0.0185

TwinsUK AF: 0.0229 AC: 85

ALSPAC AF: 0.0176 AC: 68

ESP6500AA AF: 0.00567 AC: 25

ESP6500EA AF: 0.0228 AC: 196

ExAC AF: 0.0358 AC: 4342

Asia WGS AF: 0.0660 AC: 230 AN: 3474

EpiCase AF: 0.0195

EpiControl AF: 0.0215

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Pontocerebellar hypoplasia type 6 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.021	T
Eigen	Benign	0.0015
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.70	N
PhyloP100		2.9
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.050
Sift	Benign	0.25	T
Sift4G	Benign	0.32	T
Polyphen		0.22	B
Vest4		0.067
MPC		0.10
ClinPred		0.040	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.42
Mutation Taster		=91/9	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3757370; hg19: chr6-88231226; COSMIC: COSV65762103; COSMIC: COSV65762103;