Genetic Variant RARS1:c.*66C>A (chr5-168519256-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002887.4(RARS1):c.*66C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0291 in 1,253,058 control chromosomes in the GnomAD database, including 2,446 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.043 ( 444 hom., cov: 32)

Exomes 𝑓: 0.027 ( 2002 hom. )

Consequence

RARS1
NM_002887.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.470

Publications

5 publications found

Variant links:

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

RARS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002887.4. 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.*66C>A		3_prime_UTR	Exon 15 of 15	NP_002878.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RARS1	ENST00000231572.8	TSL:1 MANE Select	c.*66C>A	3_prime_UTR	Exon 15 of 15	ENSP00000231572.3	P54136-1
RARS1	ENST00000922755.1		c.*66C>A	3_prime_UTR	Exon 15 of 15	ENSP00000592814.1
RARS1	ENST00000953515.1		c.*66C>A	3_prime_UTR	Exon 16 of 16	ENSP00000623574.1

Frequencies

GnomAD3 genomes

AF:

0.0430

AC:

6536

AN:

152080

Hom.:

442

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0370

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.183

Gnomad ASJ

AF:

0.0124

Gnomad EAS

AF:

0.125

Gnomad SAS

AF:

0.0360

Gnomad FIN

AF:

0.0431

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0115

Gnomad OTH

AF:

0.0415

GnomAD4 exome

AF:

0.0272

AC:

29891

AN:

1100858

Hom.:

2002

Cov.:

AF XY:

0.0258

AC XY:

14392

AN XY:

557344

show subpopulations

African (AFR)

AF:

0.0379

AC:

968

AN:

25520

American (AMR)

AF:

0.267

AC:

9651

AN:

36100

Ashkenazi Jewish (ASJ)

AF:

0.0111

AC:

259

AN:

23326

East Asian (EAS)

AF:

0.137

AC:

4986

AN:

36432

South Asian (SAS)

AF:

0.0337

AC:

2433

AN:

72222

European-Finnish (FIN)

AF:

0.0433

AC:

2269

AN:

52370

Middle Eastern (MID)

AF:

0.0129

AC:

AN:

4958

European-Non Finnish (NFE)

AF:

0.00974

AC:

7810

AN:

801806

Other (OTH)

AF:

0.0302

AC:

1451

AN:

48124

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1223

2445

3668

4890

6113

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

454

908

1362

1816

2270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0431

AC:

6553

AN:

152200

Hom.:

444

Cov.:

AF XY:

0.0479

AC XY:

3566

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.0372

AC:

1545

AN:

41530

American (AMR)

AF:

0.183

AC:

2804

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0124

AC:

AN:

3468

East Asian (EAS)

AF:

0.125

AC:

646

AN:

5182

South Asian (SAS)

AF:

0.0357

AC:

172

AN:

4824

European-Finnish (FIN)

AF:

0.0431

AC:

457

AN:

10598

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0115

AC:

785

AN:

67990

Other (OTH)

AF:

0.0406

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

293

586

880

1173

1466

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0208

Hom.:

199

Bravo

AF:

0.0557

Asia WGS

AF:

0.0900

AC:

313

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.74

PhyloP100

0.47

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over