chr2-135907405-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001349.4(DARS1):c.1417T>C(p.Leu473Leu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00798 in 1,608,994 control chromosomes in the GnomAD database, including 270 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 90 hom., cov: 31)

Exomes 𝑓: 0.0064 ( 180 hom. )

Consequence

DARS1
NM_001349.4 splice_region, synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.60

Publications

5 publications found

Variant links:

Genes affected

DARS1 (HGNC:2678): (aspartyl-tRNA synthetase 1) This gene encodes a member of a multienzyme complex that functions in mediating the attachment of amino acids to their cognate tRNAs. The encoded protein ligates L-aspartate to tRNA(Asp). Mutations in this gene have been found in patients showing hypomyelination with brainstem and spinal cord involvement and leg spasticity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

DARS1 Gene-Disease associations (from GenCC):

hypomyelination with brain stem and spinal cord involvement and leg spasticity
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P

DARS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

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

BP6

Variant 2-135907405-A-G is Benign according to our data. Variant chr2-135907405-A-G is described in ClinVar as [Benign]. Clinvar id is 380521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.6 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0641 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DARS1	NM_001349.4 link	c.1417T>C	p.Leu473Leu	splice_region_variant, synonymous_variant	Exon 16 of 16	ENST00000264161.9	NP_001340.2	P14868-1A0A140VJW5
DARS1	NM_001293312.1 link	c.1117T>C	p.Leu373Leu	splice_region_variant, synonymous_variant	Exon 15 of 15		NP_001280241.1	P14868-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DARS1	ENST00000264161.9 link	c.1417T>C	p.Leu473Leu	splice_region_variant, synonymous_variant	Exon 16 of 16	1	NM_001349.4	ENSP00000264161.4	P14868-1
DARS1	ENST00000422708.3 link	c.478T>C	p.Leu160Leu	splice_region_variant, synonymous_variant	Exon 6 of 6	2		ENSP00000387508.1	H7BZ35
DARS1	ENST00000478212.5 link	n.311T>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 3	2
DARS1	ENST00000489964.5 link	n.666T>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 5	2

Frequencies

GnomAD3 genomes

AF:

0.0224

AC:

3408

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0654

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0106

Gnomad ASJ

AF:

0.0228

Gnomad EAS

AF:

0.00865

Gnomad SAS

AF:

0.0333

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00304

Gnomad OTH

AF:

0.0167

GnomAD2 exomes

AF:

0.0120

AC:

2960

AN:

246774

AF XY:

0.0120

show subpopulations

Gnomad AFR exome

AF:

0.0660

Gnomad AMR exome

AF:

0.00444

Gnomad ASJ exome

AF:

0.0250

Gnomad EAS exome

AF:

0.00561

Gnomad FIN exome

AF:

0.00167

Gnomad NFE exome

AF:

0.00350

Gnomad OTH exome

AF:

0.0119

GnomAD4 exome

AF:

0.00644

AC:

9388

AN:

1456812

Hom.:

180

Cov.:

AF XY:

0.00701

AC XY:

5083

AN XY:

725006

show subpopulations

African (AFR)

AF:

0.0678

AC:

2252

AN:

33196

American (AMR)

AF:

0.00516

AC:

228

AN:

44226

Ashkenazi Jewish (ASJ)

AF:

0.0254

AC:

660

AN:

26024

East Asian (EAS)

AF:

0.0151

AC:

596

AN:

39508

South Asian (SAS)

AF:

0.0281

AC:

2414

AN:

85842

European-Finnish (FIN)

AF:

0.00148

AC:

AN:

53338

Middle Eastern (MID)

AF:

0.0162

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00213

AC:

2367

AN:

1108744

Other (OTH)

AF:

0.0116

AC:

699

AN:

60176

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

395

790

1186

1581

1976

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0227

AC:

3451

AN:

152182

Hom.:

Cov.:

AF XY:

0.0231

AC XY:

1718

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.0662

AC:

2747

AN:

41508

American (AMR)

AF:

0.0106

AC:

162

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0228

AC:

AN:

3472

East Asian (EAS)

AF:

0.00867

AC:

AN:

5188

South Asian (SAS)

AF:

0.0336

AC:

162

AN:

4824

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00304

AC:

207

AN:

68000

Other (OTH)

AF:

0.0166

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

163

327

490

654

817

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0126

Hom.:

Bravo

AF:

0.0247

Asia WGS

AF:

0.0330

AC:

115

AN:

3478

EpiCase

AF:

0.00371

EpiControl

AF:

0.00464

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Feb 15, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

5.6

(source)

DANN

Benign

0.48

PhyloP100

2.6

Mutation Taster

=97/3

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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chr2-135907405-A-G

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