rs3734908

Variant names:

• chr6-87518806-G-A
• rs3734908
• NM_020320.5:c.1305+18C>T

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.1305+18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0465 in 1,613,090 control chromosomes in the GnomAD database, including 2,130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (389 hom., cov: 31)
  • Exomes 𝑓: 0.045 (1741 hom.)
• Consequence: RARS2 NM_020320.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.305
• Publications: 6 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: Orphanet, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, PanelApp Australia
• 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 (BayesDel_noAF=-0.81).
• BP6: Variant 6-87518806-G-A is Benign according to our data. Variant chr6-87518806-G-A is described in ClinVar as Benign. ClinVar VariationId is 261219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARS2	NM_020320.5	c.1305+18C>T		intron_variant	Intron 15 of 19	ENST00000369536.10	NP_064716.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RARS2	ENST00000369536.10	c.1305+18C>T		intron_variant	Intron 15 of 19	1	NM_020320.5	ENSP00000358549.5

Frequencies

GnomAD3 genomes AF: 0.0636 AC: 9666 AN: 152046 Hom.: 387 Cov.: 31

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.0528

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.0148

Gnomad SAS AF: 0.0220

Gnomad FIN AF: 0.0208

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0479

Gnomad OTH AF: 0.0606

GnomAD2 exomes AF: 0.0424 AC: 10671 AN: 251424 AF XY: 0.0415

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.0367

Gnomad ASJ exome AF: 0.0240

Gnomad EAS exome AF: 0.0180

Gnomad FIN exome AF: 0.0228

Gnomad NFE exome AF: 0.0482

Gnomad OTH exome AF: 0.0476

GnomAD4 exome AF: 0.0447 AC: 65273 AN: 1460926 Hom.: 1741 Cov.: 32 AF XY: 0.0438 AC XY: 31822 AN XY: 726814

African (AFR) AF: 0.118 AC: 3934 AN: 33446

American (AMR) AF: 0.0387 AC: 1733 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 617 AN: 26128

East Asian (EAS) AF: 0.0207 AC: 822 AN: 39696

South Asian (SAS) AF: 0.0201 AC: 1731 AN: 86242

European-Finnish (FIN) AF: 0.0230 AC: 1227 AN: 53416

Middle Eastern (MID) AF: 0.0495 AC: 285 AN: 5762

European-Non Finnish (NFE) AF: 0.0469 AC: 52101 AN: 1111148

Other (OTH) AF: 0.0468 AC: 2823 AN: 60364

GnomAD4 genome AF: 0.0636 AC: 9674 AN: 152164 Hom.: 389 Cov.: 31 AF XY: 0.0612 AC XY: 4551 AN XY: 74394

African (AFR) AF: 0.117 AC: 4844 AN: 41496

American (AMR) AF: 0.0526 AC: 805 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0268 AC: 93 AN: 3466

East Asian (EAS) AF: 0.0151 AC: 78 AN: 5176

South Asian (SAS) AF: 0.0220 AC: 106 AN: 4814

European-Finnish (FIN) AF: 0.0208 AC: 220 AN: 10600

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0479 AC: 3257 AN: 67996

Other (OTH) AF: 0.0600 AC: 127 AN: 2116

Alfa AF: 0.0562 Hom.: 95

Bravo AF: 0.0696

Asia WGS AF: 0.0280 AC: 98 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pontocerebellar hypoplasia type 6 Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.3
DANN	Benign	0.62
PhyloP100		0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs3734908; hg19: chr6-88228524;