rs74024185

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001605.3(AARS1):c.671+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 1,613,802 control chromosomes in the GnomAD database, including 2,435 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.071 ( 1276 hom., cov: 31)

Exomes 𝑓: 0.0072 ( 1159 hom. )

Consequence

AARS1
NM_001605.3 splice_region, intron

Scores

Splicing: ADA: 0.1088

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.399

Publications

5 publications found

Variant links:

Genes affected

AARS1 (HGNC:20): (alanyl-tRNA synthetase 1) The human alanyl-tRNA synthetase (AARS) belongs to a family of tRNA synthases, of the class II enzymes. Class II tRNA synthases evolved early in evolution and are highly conserved. This is reflected by the fact that 498 of the 968-residue polypeptide human AARS shares 41% identity witht the E.coli protein. tRNA synthases are the enzymes that interpret the RNA code and attach specific aminoacids to the tRNAs that contain the cognate trinucleotide anticodons. They consist of a catalytic domain which interacts with the amino acid acceptor-T psi C helix of the tRNA, and a second domain which interacts with the rest of the tRNA structure. [provided by RefSeq, Jul 2008]

AARS1 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease axonal type 2N
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
undetermined early-onset epileptic encephalopathy
Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
developmental and epileptic encephalopathy, 29
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
trichothiodystrophy 8, nonphotosensitive
Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

AARS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 16-70271778-T-C is Benign according to our data. Variant chr16-70271778-T-C is described in ClinVar as Benign. ClinVar VariationId is 320351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.241 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AARS1	NM_001605.3 link	c.671+3A>G		splice_region_variant, intron_variant	Intron 5 of 20	ENST00000261772.13	NP_001596.2	P49588-1
AARS1	XM_047433666.1 link	c.671+3A>G		splice_region_variant, intron_variant	Intron 5 of 15		XP_047289622.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AARS1	ENST00000261772.13 link	c.671+3A>G		splice_region_variant, intron_variant	Intron 5 of 20	1	NM_001605.3	ENSP00000261772.8		P49588-1

Frequencies

GnomAD3 genomes

AF:

0.0710

AC:

10792

AN:

151940

Hom.:

1274

Cov.:

show subpopulations

Gnomad AFR

AF:

0.246

Gnomad AMI

AF:

0.0439

Gnomad AMR

AF:

0.0275

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000765

Gnomad OTH

AF:

0.0512

GnomAD2 exomes

AF:

0.0180

AC:

4524

AN:

251426

AF XY:

0.0136

show subpopulations

Gnomad AFR exome

AF:

0.247

Gnomad AMR exome

AF:

0.0105

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000484

Gnomad OTH exome

AF:

0.00766

GnomAD4 exome

AF:

0.00716

AC:

10468

AN:

1461744

Hom.:

1159

Cov.:

AF XY:

0.00623

AC XY:

4533

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.250

AC:

8370

AN:

33470

American (AMR)

AF:

0.0119

AC:

533

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26134

East Asian (EAS)

AF:

0.000126

AC:

AN:

39696

South Asian (SAS)

AF:

0.00203

AC:

175

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00835

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.000329

AC:

366

AN:

1111942

Other (OTH)

AF:

0.0161

AC:

970

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

407

814

1222

1629

2036

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

246

492

738

984

1230

<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:

0.0710

AC:

10802

AN:

152058

Hom.:

1276

Cov.:

AF XY:

0.0690

AC XY:

5124

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.245

AC:

10169

AN:

41430

American (AMR)

AF:

0.0274

AC:

419

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00104

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000765

AC:

AN:

67954

Other (OTH)

AF:

0.0530

AC:

112

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

405

810

1215

1620

2025

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

196

294

392

490

<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:

0.0387

Hom.:

303

Bravo

AF:

0.0791

Asia WGS

AF:

0.0250

AC:

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease axonal type 2N

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease type 2

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

-0.74

CADD

Benign

(source)

DANN

Benign

0.69

PhyloP100

0.40

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=48/52

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.11

dbscSNV1_RF

Benign

0.35

SpliceAI score (max)

0.040

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over