rs2305725

Variant names:

• chr5-168486454-C-A
• rs2305725
• ENST00000922754.1:c.-45C>A

Your query was ambiguous. Multiple possible variants found:

• chr5-168486454-C-A
• chr5-168486454-C-T
• chr5-168486454-C-G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000922754.1(RARS1):​c.-45C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 1,544,498 control chromosomes in the GnomAD database, including 23,704 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (1728 hom., cov: 32)
  • Exomes 𝑓: 0.17 (21976 hom.)
• Consequence: RARS1 ENST00000922754.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.99
• Publications: 14 publications found

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]

RARS1 Gene-Disease associations (from GenCC):

• hypomyelinating leukodystrophy 9

  Inheritance: Unknown, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 5-168486454-C-A is Benign according to our data. Variant chr5-168486454-C-A is described in ClinVar as Benign. ClinVar VariationId is 380049.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000922754.1. 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
	RARS1	NM_002887.4	MANE Select	c.-45C>A		upstream_gene	N/A	NP_002878.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARS1	ENST00000922754.1		c.-45C>A		5_prime_UTR	Exon 1 of 9	ENSP00000592813.1
	RARS1	ENST00000524082.5	TSL:2	n.4C>A		non_coding_transcript_exon	Exon 1 of 3
	RARS1	ENST00000231572.8	TSL:1 MANE Select	c.-45C>A		upstream_gene	N/A	ENSP00000231572.3	P54136-1

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19811 AN: 152092 Hom.: 1727 Cov.: 32

Gnomad AFR AF: 0.0321

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.0624

Gnomad SAS AF: 0.0642

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.120

GnomAD2 exomes AF: 0.129 AC: 20248 AN: 157266 AF XY: 0.129

Gnomad AFR exome AF: 0.0318

Gnomad AMR exome AF: 0.0726

Gnomad ASJ exome AF: 0.150

Gnomad EAS exome AF: 0.0528

Gnomad FIN exome AF: 0.188

Gnomad NFE exome AF: 0.187

Gnomad OTH exome AF: 0.137

GnomAD4 exome AF: 0.171 AC: 238522 AN: 1392288 Hom.: 21976 Cov.: 28 AF XY: 0.169 AC XY: 115896 AN XY: 687188

African (AFR) AF: 0.0277 AC: 875 AN: 31592

American (AMR) AF: 0.0774 AC: 2762 AN: 35668

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 3772 AN: 25120

East Asian (EAS) AF: 0.0885 AC: 3172 AN: 35862

South Asian (SAS) AF: 0.0643 AC: 5087 AN: 79120

European-Finnish (FIN) AF: 0.197 AC: 9663 AN: 49150

Middle Eastern (MID) AF: 0.0550 AC: 313 AN: 5692

European-Non Finnish (NFE) AF: 0.190 AC: 204082 AN: 1072364

Other (OTH) AF: 0.152 AC: 8796 AN: 57720

GnomAD4 genome AF: 0.130 AC: 19811 AN: 152210 Hom.: 1728 Cov.: 32 AF XY: 0.127 AC XY: 9456 AN XY: 74408

African (AFR) AF: 0.0320 AC: 1330 AN: 41550

American (AMR) AF: 0.114 AC: 1735 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 529 AN: 3472

East Asian (EAS) AF: 0.0625 AC: 323 AN: 5168

South Asian (SAS) AF: 0.0649 AC: 313 AN: 4826

European-Finnish (FIN) AF: 0.192 AC: 2040 AN: 10600

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.192 AC: 13046 AN: 68004

Other (OTH) AF: 0.121 AC: 255 AN: 2110

Alfa AF: 0.156 Hom.: 2407

Bravo AF: 0.119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.50
DANN	Benign	0.81
PhyloP100		-2.0
PromoterAI		-0.18	Neutral
Mutation Taster		=300/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2305725;

hg19: chr5-167913459;

COSMIC: COSV51563584;

COSMIC: COSV51563584;