5-168486503-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 8P and 5B. PP5_Very_Strong BP4 BS2

The NM_002887.4(RARS1):c.5A>G(p.Asp2Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000282 in 1,558,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. D2D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: RARS1 NM_002887.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.73

Genes affected

RARS1 (HGNC:9870): (arginyl-tRNA synthetase 1) Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAs, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. Arginyl-tRNA synthetase belongs to the class-I aminoacyl-tRNA synthetase family. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PP5: Variant 5-168486503-A-G is Pathogenic according to our data. Variant chr5-168486503-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 162080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.30144027).. Strength limited to SUPPORTING due to the PP5.
• BS2: High AC in GnomAd at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RARS1	NM_002887.4	c.5A>G	p.Asp2Gly	missense_variant	1/15	ENST00000231572.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RARS1	ENST00000231572.8	c.5A>G	p.Asp2Gly	missense_variant	1/15	1	NM_002887.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152116 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000420 AC: 7 AN: 166652 Hom.: 0 AF XY: 0.0000455 AC XY: 4 AN XY: 87928

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000427

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000900

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000277 AC: 39 AN: 1406664 Hom.: 0 Cov.: 30 AF XY: 0.0000302 AC XY: 21 AN XY: 694250

Gnomad4 AFR exome AF: 0.0000308

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000270

Gnomad4 SAS exome AF: 0.0000125

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152234 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74436

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.0000280 AC: 3

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypomyelinating leukodystrophy 9 Pathogenic:3

Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Nov 15, 2018	The homozygous p.Asp2Gly variant in RARS was identified by our study in one individual with Hypomyelinating Leukodystrophy. This variant has been identified in the literature in the case of two affected homozygous siblings, one girl and one boy. It has also been identified in the case of three compound heterozygous affected probands, two sisters with the variants 45+1G>T, and one unrelated proband with the variant p.Cys32TrpfsTer39. Functional studies have shown that this variant causes severely reduced function of the protein complex (Nafisinia et al. 2017, PMID: 28905880; Wolf et al. 2014, PMID: 24777941). This variant has been identified in <0.01% (6/190228) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs672601372). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for Hypomyelinating Leukodystrophy in an autosomal recessive manner based on in vitro functional studies and multiple reports of individuals with this variant and Hypomyelinating Leukodrystrophy in the literature. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 29, 2014	- -
Pathogenic, no assertion criteria provided	research	Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	-	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 08, 2023

For these reasons, this variant has been classified as Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 162080). This missense change has been observed in individual(s) with leukodystrophy (PMID: 24777941, 28905880). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs672601372, gnomAD 0.008%). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 2 of the RARS protein (p.Asp2Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.19	T;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.42	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.32	N;.
MutationTaster	Benign	0.50	D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.5	N;.
REVEL	Pathogenic	0.74
Sift	Benign	0.18	T;.
Sift4G	Benign	0.51	T;T
Polyphen		0.0	B;.
Vest4		0.31
MutPred		0.22		Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);
MVP		0.57
MPC		0.17
ClinPred		0.18	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.58
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs672601372; hg19: chr5-167913508;