Genetic Variant DARS1:c.-34+73C>A (chr2-135985740-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The ENST00000441323.5(DARS1):c.-34+73C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00876 in 798,368 control chromosomes in the GnomAD database, including 536 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0076 ( 99 hom., cov: 33)

Exomes 𝑓: 0.0090 ( 437 hom. )

Consequence

DARS1
ENST00000441323.5 intron

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.310

Publications

4 publications found

Variant links:

COSMIC-nc: COSV51539641

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 links:

DARS1-AS1 (HGNC:40170): (DARS1 antisense RNA 1)

DARS1-AS1 links:

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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=-0.67).

BP6

Variant 2-135985740-G-T is Benign according to our data. Variant chr2-135985740-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1202907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000441323.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
DARS1-AS1	NR_110199.1		n.341+224G>T	intron	N/A
DARS1-AS1	NR_110200.1		n.341+224G>T	intron	N/A
DARS1	NM_001349.4	MANE Select	c.-272C>A	upstream_gene	N/A	NP_001340.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DARS1	ENST00000441323.5	TSL:3	c.-34+73C>A	intron	N/A	ENSP00000389867.1	C9JLC1
DARS1	ENST00000456565.5	TSL:3	c.-34+190C>A	intron	N/A	ENSP00000397616.1	C9J7S3
DARS1	ENST00000449218.5	TSL:3	c.-34+54C>A	intron	N/A	ENSP00000388801.1	C9JQM9

Frequencies

GnomAD3 genomes

AF:

0.00765

AC:

1164

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.195

Gnomad SAS

AF:

0.0110

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.00669

GnomAD4 exome

AF:

0.00902

AC:

5826

AN:

646044

Hom.:

437

Cov.:

AF XY:

0.00880

AC XY:

2867

AN XY:

325938

show subpopulations

African (AFR)

AF:

0.000123

AC:

AN:

16236

American (AMR)

AF:

0.000566

AC:

AN:

17654

Ashkenazi Jewish (ASJ)

AF:

0.00804

AC:

114

AN:

14174

East Asian (EAS)

AF:

0.166

AC:

4909

AN:

29604

South Asian (SAS)

AF:

0.00618

AC:

288

AN:

46584

European-Finnish (FIN)

AF:

0.000453

AC:

AN:

26492

Middle Eastern (MID)

AF:

0.000887

AC:

AN:

2254

European-Non Finnish (NFE)

AF:

0.000297

AC:

137

AN:

461432

Other (OTH)

AF:

0.0111

AC:

352

AN:

31614

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

229

458

686

915

1144

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

234

312

390

<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:

0.00764

AC:

1164

AN:

152324

Hom.:

Cov.:

AF XY:

0.00875

AC XY:

652

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.000192

AC:

AN:

41578

American (AMR)

AF:

0.000914

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00778

AC:

AN:

3470

East Asian (EAS)

AF:

0.195

AC:

1009

AN:

5172

South Asian (SAS)

AF:

0.0110

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000753

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000382

AC:

AN:

68026

Other (OTH)

AF:

0.00851

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

100

150

200

250

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.000621

Hom.:

Bravo

AF:

0.00946

Asia WGS

AF:

0.0720

AC:

251

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

7.3

(source)

DANN

Benign

0.87

PhyloP100

0.31

PromoterAI

0.19

Neutral

(source)

Splicing

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