dbSNP rs2278681: DARS1:c.66+34A>G (chr2-135985369-T-C) – 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 NM_001349.4(DARS1):c.66+34A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0263 in 1,609,920 control chromosomes in the GnomAD database, including 2,003 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.050 ( 378 hom., cov: 32)

Exomes 𝑓: 0.024 ( 1625 hom. )

Consequence

DARS1
NM_001349.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.222

Publications

4 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 links:

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

DARS1-AS1 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=-0.77).

BP6

Variant 2-135985369-T-C is Benign according to our data. Variant chr2-135985369-T-C is described in ClinVar as Benign. ClinVar VariationId is 1258838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001349.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DARS1	NM_001349.4	MANE Select	c.66+34A>G	intron	N/A	NP_001340.2
DARS1	NM_001293312.1		c.-177+34A>G	intron	N/A	NP_001280241.1	P14868-2
DARS1-AS1	NR_110199.1		n.194T>C	non_coding_transcript_exon	Exon 1 of 4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DARS1	ENST00000264161.9	TSL:1 MANE Select	c.66+34A>G	intron	N/A	ENSP00000264161.4	P14868-1
DARS1	ENST00000952144.1		c.66+34A>G	intron	N/A	ENSP00000622203.1
DARS1	ENST00000952145.1		c.66+34A>G	intron	N/A	ENSP00000622204.1

Frequencies

GnomAD3 genomes

AF:

0.0500

AC:

7612

AN:

152174

Hom.:

380

Cov.:

show subpopulations

Gnomad AFR

AF:

0.101

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.0815

Gnomad ASJ

AF:

0.0225

Gnomad EAS

AF:

0.0894

Gnomad SAS

AF:

0.159

Gnomad FIN

AF:

0.0103

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.00882

Gnomad OTH

AF:

0.0526

GnomAD2 exomes

AF:

0.0486

AC:

11874

AN:

244276

AF XY:

0.0496

show subpopulations

Gnomad AFR exome

AF:

0.0999

Gnomad AMR exome

AF:

0.0872

Gnomad ASJ exome

AF:

0.0233

Gnomad EAS exome

AF:

0.0737

Gnomad FIN exome

AF:

0.00931

Gnomad NFE exome

AF:

0.0107

Gnomad OTH exome

AF:

0.0363

GnomAD4 exome

AF:

0.0238

AC:

34753

AN:

1457630

Hom.:

1625

Cov.:

AF XY:

0.0267

AC XY:

19331

AN XY:

724882

show subpopulations

African (AFR)

AF:

0.103

AC:

3432

AN:

33448

American (AMR)

AF:

0.0866

AC:

3848

AN:

44458

Ashkenazi Jewish (ASJ)

AF:

0.0224

AC:

580

AN:

25908

East Asian (EAS)

AF:

0.0993

AC:

3937

AN:

39652

South Asian (SAS)

AF:

0.135

AC:

11547

AN:

85836

European-Finnish (FIN)

AF:

0.00928

AC:

484

AN:

52180

Middle Eastern (MID)

AF:

0.0501

AC:

287

AN:

5732

European-Non Finnish (NFE)

AF:

0.00777

AC:

8624

AN:

1110192

Other (OTH)

AF:

0.0334

AC:

2014

AN:

60224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

1780

3560

5341

7121

8901

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

540

1080

1620

2160

2700

<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:

0.0499

AC:

7602

AN:

152290

Hom.:

378

Cov.:

AF XY:

0.0532

AC XY:

3962

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.101

AC:

4199

AN:

41562

American (AMR)

AF:

0.0812

AC:

1243

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0225

AC:

AN:

3472

East Asian (EAS)

AF:

0.0898

AC:

466

AN:

5188

South Asian (SAS)

AF:

0.157

AC:

760

AN:

4828

European-Finnish (FIN)

AF:

0.0103

AC:

109

AN:

10618

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00884

AC:

601

AN:

68000

Other (OTH)

AF:

0.0521

AC:

110

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

365

731

1096

1462

1827

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

188

282

376

470

<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:

0.0363

Hom.:

111

Bravo

AF:

0.0536

Asia WGS

AF:

0.132

AC:

458

AN:

3478

ClinVar

ClinVar submissions

Significance: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

-0.77

CADD

Benign

8.7

(source)

DANN

Benign

0.75

PhyloP100

-0.22

PromoterAI

0.085

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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